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Physiol Rev 92: 739 –789, 2012 doi:10.1152/physrev.00004.2011 NUCLEAR HORMONE RECEPTORS ENABLE MACROPHAGES AND DENDRITIC CELLS TO SENSE THEIR LIPID ENVIRONMENT AND SHAPE THEIR IMMUNE RESPONSE Laszlo Nagy, Attila Szanto, Istvan Szatmari, and Lajos Széles Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, and Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary L I. II. III. IV. V. VI. VII. VIII. IX. X. XI. INTRODUCTION MACROPHAGES ARE IMMUNE... THE MAIN FUNCTIONS FOR DENDRITIC... RXR AND ITS PARTNERS: RAR,... THE BIOLOGY OF RAR AND RXR... THE BIOLOGY OF LXR IN... THE BIOLOGY OF PPAR␥... THE BIOLOGY OF VDR IN... COMPLEXITY OF GENE REGULATION... LIGAND PRODUCTION BY DENDRITIC... CONCLUSIONS AND PERSPECTIVES 739 740 746 748 752 755 757 765 768 769 773 I. INTRODUCTION The fate of cells is largely determined by the quantitative and qualitative gene expression changes, which are taking place as the result of alterations in endo- and exoge- nous signaling. It is becoming increasingly clear that the major direct initiators and regulators of such changes are transcription factors, which can bring about the changes necessary to alter cellular differentiation and cell fates. Probably the most well-documented cases of cell fate determination processes are examples of cellular differentiation. During these processes, a coordinated set of signals govern the differentiation and cell type specification of stem and/or progenitor cells into diverse directions. Conceptually, a fairly well understood system is the differentiation of bone marrow-derived myeloid progenitor cells of the immune system such as macrophages or dendritic cells (DCs) (151, 169) amongst others. These cell types are particularly intriguing because they are not just key components of the immune system, but are also pres- 739 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Nagy L, Szanto A, Szatmari I, Széles L. Nuclear Hormone Receptors Enable Macrophages and Dendritic Cells to Sense Their Lipid Environment and Shape Their Immune Response. Physiol Rev 92: 739 –789, 2012; doi:10.1152/physrev.00004.2011.—A key issue in the immune system is to generate specific cell types, often with opposing activities. The mechanisms of differentiation and subtype specification of immune cells such as macrophages and dendritic cells are critical to understand the regulatory principles and logic of the immune system. In addition to cytokines and pathogens, it is increasingly appreciated that lipid signaling also has a key role in differentiation and subtype specification. In this review we explore how intracellular lipid signaling via a set of transcription factors regulates cellular differentiation, subtype specification, and immune as well as metabolic homeostasis. We introduce macrophages and dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate gene expression upon receiving lipid signals. The receptors we cover are the ones with a recognized physiological function in these cell types and ones which heterodimerize with the retinoid X receptor. These are as follows: the receptor for a metabolite of vitamin A, retinoic acid: retinoic acid receptor (RAR), the vitamin D receptor (VDR), the fatty acid receptor: peroxisome proliferator-activated receptor ␥ (PPAR␥), the oxysterol receptor liver X receptor (LXR), and their obligate heterodimeric partner, the retinoid X receptor (RXR). We discuss how they can get activated and how ligand is generated and eliminated in these cell types. We also explore how activation of a particular target gene contributes to biological functions and how the regulation of individual target genes adds up to the coordination of gene networks. It appears that RXR heterodimeric nuclear receptors provide these cells with a coordinated and interrelated network of transcriptional regulators for interpreting the lipid milieu and the metabolic changes to bring about gene expression changes leading to subtype and functional specification. We also show that these networks are implicated in various immune diseases and are amenable to therapeutic exploitation. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES to mediate lipid signaling at the level of gene expression (318). Due to the fact that these transcription factors are intimately linked to lipid metabolism, they represent an important crossroad between lipid metabolism and immune function (161, 211, 503). In this review, we focus on a selected group of nuclear hormone receptors, RXR heterodimers (318) (TABLE 1) and evaluate the available evidence on how activation of these receptors can modulate cell fate decisions in macrophages and DCs. How these pathways are interacting with cytokine signaling and how these might be linked to disease states such as atherosclerosis, inflammation, and host response to pathogens will also be discussed. As a general principle, the differentiation and specification of these cells are regulated by endogenous and exogenous stimuli, including cytokines and TLR ligands, respectively (151, 168, 169) (FIGURE 1). However, it is increasingly appreciated that changes in the lipid environment also contribute to cell type differentiation and specification mainly by alterations of transcriptional responses. II. MACROPHAGES ARE IMMUNE CELLS WITH DIVERSE BIOLOGICAL FUNCTIONS In multicellular organisms, a distinct set of transcription factors, the superfamily of nuclear receptors, have evolved A. Macrophages Are More Than Just “Big Eaters” It was more than 100 years ago when Elie Metchnikoff discovered macrophages (␣ ⫽ large and ␣␥⑀ ⫽ eat) and assigned phagocytosis as their major function FIGURE 1. The impact of endogenous and exogenous stimuli including nuclear receptor ligands on macrophages and dendritic cells. Schematic representation of the principles of macrophage/dendritic cell differentiation from precursors. Host-derived and pathogen-derived stimuli trigger and regulate the activation/maturation of the precursor cells (monocytes, non-activated macrophages, and immature dendritic cells). The way of activation/maturation of the effector cells (activated macrophages and mature dendritic cells) depends on the input signals and the signal integration. Some stimuli, e.g., Toll-like receptor (TLR) ligands and proinflammatory cytokines can initiate subtype specification. Other stimuli, e.g., nuclear receptor ligands, typically do not trigger these processes, but they have the capacity to modify or antagonize the activation/maturation programs. For simplicity, this schematic representation does not illustrate many aspects of the influence of stimuli on macrophages and dendritic cells. For example, many nuclear receptor ligands are more efficient if they act before inflammatory stimuli (“reprogramming”). Subtype specification itself is also more complex than it is represented here, e.g., not all dendritic cell subtypes have to undergo maturation to fulfill their function. 740 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 ent in all tissues and many compartments of the body representing a wide array of subtype specification pathways such as classically and alternatively activated macrophages, different tissue macrophages, Kupffer cells, alveolar macrophages, microglia, or among DCs plasmacytoid and conventional DCs, such as Langerhans cells (151, 169). Importantly, these cell types are often exposed to large amounts of lipids, including pathogen- and host-derived lipoproteins or lipids of apoptotic cells; therefore, they represent a well-suited model to study and understand the regulatory principles and logic of the integration of lipid and inflammatory signaling with gene expression at the cellular level (503). Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Most common/canonical responsive elements Transcriptional unit Examples of synthetic ligands Proposed/prototypic natural ligands Main physiological functions Differentiation Binding partner for other nuclear receptors, differentiation 9-cis retinoic acid, doxosahexonoic acid, phytanic acid Rexinoids, e.g., LG100268 Many heterodimers and probably homodimer According to the partner preference, DR-1 for homodimer RAR (NR1B2 ): ubiquitously expressed RAR␥ (NR1B3 ): ubiquitously expressed RXR (NR2B2): ubiquitously expressed RXR␥ (NR2B3): ubiquitously expressed DR-5 DR-4 Permissive heterodimer T0901317 TTNPB Conditional heterodimer GW3965 Oxysterols Cholesterol metabolism LXR␣ (NR1H3): liver, adipose tissue, intestine, lung, kidney, adrenal glands, and macrophages LXR (NR1H2): ubiquitously expressed Liver X Receptors (LXRs) AM580 9-cis retinoic acid, all-trans retinoic acid RAR␣ (NR1B1): ubiquitously expressed RXR␣ (NR2B1): ubiquitously expressed Retinoic Acid Receptors (RARs) Nonpermissive heterodimer ␥: Thiazolidinediones, NPC15199, GW1929, GW7845 ␦: GW501516,GW0742 Dual agonists Permissive heterodimer DR-3 MC903 (calcipotriol) ␣: WY14643, GW7647, AM3102 DR-1 1␣,25-Dihydroxyvitamin D3 Calcium metabolism and bone homeostasis VDR (NR1I1): highly expressed in the gastrointestinal system, with moderate levels in the kidney, thyroid, bone, and skin Vitamin D Receptor (VDR) Polyunsaturated and oxidized fatty acids PPAR (NR1C2), also called PPAR␦: ubiquitously expressed PPAR␥ (NR1C3): white adipose tissue, macrophages, and dendritic cells Lipid metabolism PPAR␣ (NR1C1): expressed mainly in in metabolic tissues (brown adipose tissue, liver, and kidney) Peroxisome Proliferator Activated Receptors (PPARs) Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Isotypes and tissue distribution Retinoid X Receptors (RXRs) Table 1. Summary of nuclear receptor localization and activity NAGY ET AL. 741 NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES (253). Today macrophages represent a very heterogeneous and highly specialized cell population (151). They are involved in many steps of innate and adaptive immune responses, being essential players in antigen presentation, wound healing, elimination of bacteria, removal of necrotic cellular debris, and secretion of cytokines. Moreover, several lines of evidence support a central role for macrophage-mediated inflammation in the pathogenesis of metabolic diseases, most importantly atherosclerosis, but also in diabetes and metabolic syndrome (163, 392). B. Development of Monocytes/Macrophages CD34⫹ stem cells can give rise to every cell type in the blood. Traditionally, it was believed that monocytes develop from common myeloid progenitors of granulocytes and monocytes termed colony-forming units (CFUs); therefore, the generation of monocytes is part of the general differentiation process of myeloid cells, termed myelopoiesis. Differentiation starts from stem cells with the formation of granulocyte, erythrocyte, monocyte, and megakaryocyte colony forming unit (CFU-GEMM), which give rise to granulocyte, macrophage colony-forming unit (CFU-GM) upon the effect of granulocyte-macrophage colony stimulating factor (GM-CSF). Subsequently, macrophage colony-forming unit (CFU-M or CMP ⫽ common myeloid precursor) is induced by macrophage colony-stimulating factor (MCSF). This develops into monoblast and later promonocyte to finally give rise to monocytes (144, 145). However, the relationship between the origin of monocytes and dendritic cells remains controversial. The existence of a common precursor monocyte DC precursor (MDP) has been shown, but its relationship to common DC precursor (CDP) is still unresolved (see also sect. IIIB) (139). There are distinct types of monocytes in the blood: 1) classical monocytes are characterized as CD14⫹⫹CD16⫺ while 2) nonclassical monocytes show low CD14 and high CD16 cell surface expression (CD14⫹CD16⫹⫹) (595). Recent nomenclature distinguishes a third category as well termed intermedier monocytes (CD14⫹⫹ CD16⫹) (569). CD14⫹CD16⫹⫹ monocytes express CC-chemokine receptor 5 (CCR5), whereas CD14⫹⫹CD16⫺ monocytes express CCR2 (557). This pattern is characteristic for human monocytes. However, murine monocytes are also heteroge- 742 Monocytes can migrate through the endothelium of blood vessels upon various stimuli. During this extravasation they undergo several changes to become macrophages or DCs. Monocytes/macrophages can be characterized by the high level of CD14, CD11b, CD36, CD68 and F4/80 in mice or by epidermal growth factor-like module containing, mucinlike, hormone receptor-like 1, also known as EMR1, lysozyme M, macrophage antigen-1/3, and M-CSF receptor. The major function of monocytes is related to the immune system: once they differentiate into macrophages and inflammatory DCs, they are either attracted to inflammatory sites or survey the tissues for foreign/accumulated molecules and pathogens to engulf. In response to inflammatory stimuli, monocytes are rapidly recruited to the sites of inflammation where they are involved not only in the killing/ elimination of such particles but evoke specific signaling processes to activate further immune mechanisms. Macrophages are also capable of activating adaptive immune responses, whilst DCs are considered to be more efficient in this. Another important role for macrophages stems from their potency on metabolizing lipid molecules. Probably as part of its original protective role against foreign substances, macrophages are also capable of recognizing lipid molecules when accumulating within the tissues. This process linked macrophages to metabolism, and roles have been assigned for them in the process of atherosclerosis and lipid storage diseases. Recently, by studying the crosstalk of immune system and lipid metabolism, macrophages have been involved in the process of obesity and insulin resistance as particular cell types regulating lipid metabolism and inflammation in adipose tissue (392; for details, see below). The differentiation of myeloid cells is principally regulated by cytokines and orchestrated via cooperative gene regulation by transcription factors. The most important players are PU.1, CCAAT/enhancer binding proteins (C/EBPs), and AP-1. For a detailed overview of transcriptional control of granulocyte and monocyte development, we refer to other reviews (144, 145). Briefly, at early stages of hematopoiesis, PU.1 directs stem cells to the lymphoid-myeloid lineage by inhibiting megakaryocyte-erythroid differentiation via interacting with GATA-binding protein (227, 330, 465). In the next step C/EBP␣ inhibits lymphoid, whilst induces granulocyte-monocyte development (589, 590). PU.1 again induces monocytic commitment (107, 278). PU.1 itself is induced by C/EBP␣ (550) and activated by c-Jun (37). C/EBP␣ together with c-Jun or c-Fos favors monocytic development (294, 308, 496), which is further assisted by protein kinase C (PKC), Egr-1, Egr-2, VDR, MafB/c, and Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Monocytes constitute ⬃3– 8% of circulating leukocytes and are produced in the bone marrow from hematopoietic stem cell progenitors. After differentiation they are released into the circulation from where they move into tissues usually within 1–3 days. According to a recent report, there is a reservoir for monocytes in the spleen where they form clusters in the cords of the subcapsular red pulp (495). neous. CCR2⫹CX3CR1low cells correspond to the human CD14⫹⫹CD16⫺ inflammatory monocytes, while resident monocytes are CCR2⫺CX3CR1hi, corresponding to the human CD14⫹CD16⫹⫹ cells (152, 169). NAGY ET AL. interferon regulatory factor 8, while RAR and C/EBP⑀ direct granulopoiesis. Phorbol esters are widely used as inducers of monocytic maturation of myeloid cell lines. They activate PKC-␣, which in turn activates c-Jun kinase 2, that will activate c-Jun and induce monocytic maturation (413). C. Macrophage Activation and Function in Innate Immunity As a result of their studies on mannose receptor, Gordon and colleagues (484) discovered another class of activated macrophages, which they termed alternatively activated macrophages (or M2 on FIGURE 4C). Alternative macrophages, in contrast to the classically activated cells, express high levels of mannose receptor and exert an almost opposite immunophenotype. They cannot produce nitrogenmonoxide and radicals required for killing, they inhibit T However, a growing body of evidence suggests that the group of nonclassically activated macrophages itself is heterogeneous and exhibits significant differences in their biochemistry and physiology. Therefore, some authors suggest that, based on their functions, macrophages should be classified into three major groups: classically activated macrophages (playing important roles in host defence), wound healing macrophages, and regulatory macrophages. In addition to these categories, there are macrophages that share characteristics of two groups, e.g., tumor-associated macrophages, which have many characteristics of regulatory macrophages but also share some characteristics of wound-healing macrophages (353, 354). D. Antigen Presentation by Macrophages: Induction of Acquired Immunity Macrophages phagocytose self-proteins and cells during normal tissue repair and aging. These self-proteins do not activate T cells, because in the absence of infection, macrophages in general express low levels of major histocompatibility complex (MHC)-II and costimulatory molecules. However, lipopolysaccharide (LPS) and various cytokines stimulate macrophages to upregulate MHC-II and B7 (CD80 and CD86 together) molecules, providing these cells with strong antigen presentation properties. This is complemented by their ability to uptake and process antigens. In addition, macrophage activation results in upregulation of cytokines such as IL-1, IL-6, IL-8, IL-12, and TNF (324, 529). With these capacities, macrophages are able to activate memory and effector T cells, but not naive T cells. Interestingly, a subset of specialized macrophages (subcapsular sinus macrophages) contribute to early delivery of antigens to B cell follicules at the subcapsular sinus of Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 743 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Macrophages are central players of innate immunity not only because they eliminate pathogens, cellular debris, and senescent and dying cells, but they also produce a range of secretory products, which affect the migration and activity of other immune cells. Macrophages are inherently heterogeneous, as they need to respond to a variety of signals in very different tissue contexts. One level of heterogeneity originates from the localization of the resident macrophages. There are specialized macrophages with more or less different functions, like Kupffer cells in the liver, microglia in the central nervous system, osteoclasts in the bone, alveolar macrophages in the lung, perivascular macrophages, and Hofbauer cells in the placenta, etc. (168, 169) (FIGURE 2). Another level of heterogeneity is initiated by environmental signals, most importantly cytokines and pathogen-derived molecules. Initially, activated macrophages were defined as cytokine-producing cells that are able to kill pathogens (108). However, the changing inflammatory milieu could result in distinct activation of cells leading to subpopulations with specialized functions. The distinct functions require highly specialized cells, which are differentiated upon cytokines and microbial products (312). Pro-inflammatory molecules like interferon-gamma (IFN-␥), tumor necrosis factor (TNF), and activators of pattern recognition molecules like Toll-like receptors (TLRs) induce the so-called classical activation of macrophages (classically activated macrophages, or M1 on FIGURE 4C). Consequently, macrophages migrate to the sites of inflammation to engulf and degrade pathogens by producing nitrogen-monoxide and radicals. They also secrete proinflammatory molecules such as TNF, interleukin (IL)-1, IL-6, and MCP-1 to sustain the inflammatory reaction. This classical pathway of IFN-␥-dependent macrophages activation provokes Th1-type responses and serves as an efficient arm of innate immunity directed against intracellular pathogens, like Listeria monocytogenes or Mycobacterium tuberculosis (165, 353). cell proliferation (459), and they provoke immunotolerance or Th2 immune responses (104). They can also produce anti-inflammatory molecules such as transforming growth factor (TGF)-, IL-10, or IL-1 receptor antagonist (138, 165, 459) and inhibit the secretion of pro-inflammatory molecules such as IL-1, TNF, IL-6, IL-12, and macrophage inhibitory protein (MIP)-1␣ (50, 86, 482). Alternatively activated macrophages can be characterized by high levels of mannose receptor (484), CD23 (34), alternative macrophage activation-associated chemokine 1 (AMAC-1 or CCL18) (264), arginase-1 (361), FIZZ1, and YM1, (421). The alternative activation of macrophages is induced by Th2 cytokines IL-4 and IL-13 and results in a distinct macrophage subpopulation with roles in humoral immunity and resolution such as repair, wound healing, angiogenesis, tissue repair, and extracellular matrix deposition (164, 168, 173, 264, 265, 353). Under in vivo conditions, alternatively activated macrophages are found at border surfaces in the body such as lung, placenta, and perivascular space (75, 136, 264, 300, 358). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 744 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org NAGY ET AL. lymph nodes (69, 411) by collecting and distributing native antigens. It should be mentioned that macrophages, in particular, alveolar macrophages and tumor-associated macrophages, have been linked to suppression of T cells as well (363, 577). Clearly, macrophage subtype specification has an important role in determining the direction of the immune response, and thus macrophages are important amplifiers of the adaptive immune response. E. Macrophages in Metabolic Processes Vessels are covered by a single cell layer, the endothelium, that serves as a barrier between the circulating blood and subendothelial tissues. Molecules and cells have to migrate through this layer to reach their destination in a regulated fashion. Preferred sites where atherosclerotic lesion starts to develop are places with vulnerable endothelium, i.e., where the cell layer is injured or gets injured easier than at other sites. A disturbance in the laminar flow of blood is, for example, one such factor that increases endothelial vulnerability. Independently of the cause, endothelial dysfunction Macrophages are considered to be the first cellular components in lesion formation. They take up lipid particles through specialized cell surface proteins termed scavenger receptors (SRs), such as SR-A and CD36. Importantly, these scavenger receptors are not subjected to downregulation via a negative-feedback mechanism such as in the case of LDL receptor. Consequently, the more lipid molecules that are present, the higher the lipid concentration in the cells will be leading to the appearance of the characteristic macrophage subtype, the lipid-loaded foam cells. These cells can be identified already in the fatty streaks. Macrophages not only take up lipid particles from the environment, but they metabolize them and eliminate lipids through their ATP-binding cassette transporters such as ABCA1 and ABCG1 towards high-density lipoprotein (HDL). If there is an imbalance between the amount of lipids taken up and the metabolizing/effluxing capacity of the macrophages, they start accumulating lipids resulting in increased cell death and sustained chronic inflammation (163, 190, 298). As a consequence of the chronic inflammation, smooth muscle cells migrate from the tunica media and go through a fibroblast-like transformation resulting in proliferation and production of extracellular matrix elements. This leads to the formation of the late, fibrous atherosclerotic plaques. If calcification (sclerosis) occurs, the artery wall becomes rigid and fragile. Finally, the originally stable lesion may change FIGURE 2. Development and in vitro models of macrophages and dendritic cells (DC). A: development and the most important subtypes of macrophages and DC. Macrophages and DC can be found in many tissues, and they can play different functions. Conventional DC, plasmacytoid DC, and monocytes share a common progenitor, the macrophage and DC precursor (MDP). However, recent data indicate that some macrophage and DC subtypes, e.g., microglial cells and Langerhans cells, are not necessarily derived from this common bone marrow progenitor. B: in the two most common in vitro models, macrophages and DC are differentiated from murine bone marrow cells and human monocytes in the presence of growth factors and cytokines. Activated macrophages and mature DCs usually are obtained by using Toll-like receptor (TLR) ligands and/or various cytokines. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 745 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 There is a rich array of interactions between inflammation and metabolism. Pathogens and inflammation itself could disturb metabolic processes, and vice versa, chronic metabolic diseases could lead to abnormal immune reactions. In some cases, it is hard to deconvolute what is cause and what is consequence. Metabolic syndrome, a constellation of metabolic abnormalities including insulin resistance, hypertension, dyslipidemia, and central obesity, is very often coupled to atherosclerosis, a progressive, degenerative disease of blood vessels. Atherosclerosis is a good example of the intersection of metabolic and immune processes, especially if one considers the pivotal role of macrophages. The progression of the atherosclerotic lesion starts after birth, and generally, the first clinical manifestations occur in the sixth decade of life. Complications of atherosclerosis such as ischemic heart disease, myocardial infarction, and stroke make atherosclerosis responsible for most of the deaths in western societies. The first sign of lesion formation in the vessel wall is the lipid/cholesterol accumulation observed by the appearance of fatty streaks within the subintimal tissues (175) (FIGURE 6). Cholesterol accumulation is driven by pathogenic interaction between circulating lipoproteins, hemodynamic factors, endothelial cells, vascular smooth muscle cells, macrophages, and T lymphocytes and results from the abnormal handling of lipids by macrophages (163, 311, 475). results in the accumulation of low-density lipoprotein (LDL) in the subendothelial matrix (311). It is not clear how LDL gets modified, but this leads to the appearance of minimally oxidized/modified LDL (mmLDL) and subsequently fully oxidized LDL (oxLDL) containing multiple oxidized lipid molecules (163). Oxidatively modified lipoproteins and lipids can activate both endothelial cells and monocytes/macrophages leading to the migration of monocytes into the subendothelial space (420). Here, macrophages start taking up and clearing up the accumulating lipid particles. However, this might be incomplete and/or the continuous supply from the circulation overloads the lipid handling capacity of the macrophages leading to chronic inflammation with further accumulation of lipids and involvement of multiple cell types, such as endothelial cells, additional macrophages, granulocytes, lymphocytes, fibroblasts, and smooth muscle cells from the media of the vessel. The release of inflammatory mediators and chemoattractants by these cells evokes a characteristic inflammatory response around lipid accumulation by attracting additional cells to the lesion (377, 420, 485). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES into an unstable vulnerable plaque that can easily rupture the endothelium leading to the formation of thrombus and intravascular coagulation. Nuclear receptors, most importantly PPAR␥ and LXRs, have been implicated in the regulation of lipid metabolism in several cell types contributing to lesion initiation, development, and progression. These include macrophages, fibroblasts, T lymphocytes, smooth muscle cells, and endothelial cells. We will detail the role and contribution of PPAR␥ and LXR in the formation of atherosclerotic lesions (41, 73, 161, 211, 501, 523) in sections VI and VII. According to some reports, more than 40% of the total adipose tissue cell content from obese rodents and humans can be macrophages, while in lean counterparts this value is ⬃10% (559). The suggestion is that adipose tissue macrophages or ATMs are the major sources of cytokines, which can function as paracrine and/or endocrine mediators of inflammation leading to decreased insulin sensitivity. It is believed that activation of macrophages leads to the production and release of chemokines and cytokines such as IL-1, TNF-␣ and IL-6. This leads to the activation of Jun NH2-terminal kinase (JNK) (29, 202), inhibitor of B kinase  (IKK), and other kinases (224). The insulin-resistant state is characterized by increased JNK and IKK levels in adipose tissue and skeletal muscle. This in turn leads to activation of AP-1 and NF-B and the subsequent transcriptional activation of inflammatory genes. Insulin receptor substrate also gets phosphorylated, leading to cellular insulin resistance. Nuclear receptors, most prominently PPAR␥, have been linked to these macrophages and to disease progression as it will be discussed in section VII. 746 A. Antigen Presentation by Dendritic Cell Is a Key Step in Engaging the Adaptive Immune Response Traditionally, macrophages and B cells were thought to be the only cell types able to present antigens to T cells and thus elicit immune response. However, Steinman and Cohn (487) showed that another kind of antigen-presenting cell types, DCs, are indispensable for the initiation of the adaptive immune response (28). DCs can be considered as effector cells with the potential to interact with lymphocytes and regulate their function (430). DCs also play an important role in innate immune responses, e.g., plasmacytoid DCs produce type I IFNs in response to viral infection, while TNF-␣/inducible nitric oxide synthase (iNOS)-producing DCs mediate defense against bacterial infection (466, 486). Moreover, in addition to eliciting immune response, DCs could also provoke immunological tolerance by inducing deletion or anergy; thus DCs contribute to limiting autoimmunity (96). DCs can be found in lymphoid organs, in the blood, at body surfaces (e.g., the skin, pharynx, upper esophagus, vagina, and anus), and at mucosal surfaces such as the respiratory and gastrointestinal system (486) (FIGURE 2). Importantly, DCs can be generated in vitro from precursors found in the bone marrow, spleen, or blood (monocyte-derived DC), allowing studies using large amount of cells (222, 452, 568) (FIGURE 2). Similarly to macrophages, DCs form a heterogeneous cell population, and DC subsets differ in function, location, migratory pathways, and activation status. Remarkably, we do not have any good phenotypic markers specific to DCs, nor any functional criteria; therefore, the clear distinction of DCs from macrophages is still problematic (151, 220). Early studies, using mainly Langerhans cells (DCs in the epidermis), demonstrated that DCs exist in two states: “off” (immature) and “on” (mature) (430). The paradigmatic Langerhans cell life cycle and migratory pathways were modeled based on studies carried out in the 1980s (246, 430, 540, 567). According to this model, migratory DCs such as Langerhans cells, work at the interface of peripheral tissues. These cells are sentinels of the immune system, and they sense and translate environmental cues by sampling and processing extracellular and intracellular antigens. DCs uptake antigen by various mechanisms (383, 456) and migrate to lymph nodes, where they present antigens and stimulate T cells. The pathogen-derived signals, pro-inflammatory cytokines, and danger signals all integrated by DCs and define the immune response. These ac- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Another metabolic condition in which the involvement of macrophages has been highlighted in recent years is metabolic syndrome itself (for a review, see Ref. 392). It is an emerging concept that inflammation appears to be a component of obesity-associated insulin resistance. Several lines of evidence including genetic as well as pharmacological inhibition of pathways contributing to inflammatory responses were found to protect against diet-induced insulin resistance. In addition, it has been shown that chronic activation of intracellular pro-inflammatory pathways in target tissues of insulin leads to obesityrelated insulin resistance. Another relevant feature of the disease condition is that macrophages are present in adipose tissue of obese individuals more than in lean ones. Moreover, these cells appear to be the major sources of inflammatory cytokines linked to insulin resistance such as TNF-␣ (213, 460). Since it has been suggested that adipose tissue from obese mice and humans are infiltrated with increasing number of macrophages (560, 571), it represents a major new paradigm potentially explaining the disease process. III. THE MAIN FUNCTIONS FOR DENDRITIC CELLS ARE ANTIGEN PRESENTATION AND LYMPHOCYTE ACTIVATION NAGY ET AL. tivating stimuli lead to the maturation of DCs and promote the transition from an “antigen-sampling mode” to the “antigenpresenting mode” (430). Mature DCs deliver three types of signals that are thought to be essential to initiate T-cell activation and determine the fate of naive T cells: antigen presentation (signal 1), costimulation (signal 2), and polarizing cytokines (signal 3) (247, 430). The “Langerhans cell paradigm” has been a guiding principle in DC research (246, 430, 540, 567). However, it is clear now that this model does not describe the function and life cycle of several DC subsets. Three examples are given here to illustrate the functional heterogeneity of DCs and the differences from the original paradigm. Second, DCs in secondary lymphoid tissues are not necessarily mature and not derived from cells previously resident in peripheral tissues. Instead, many DCs in the spleen and lymph nodes, especially in the steady state, are immature and derived from blood-born progenitors (430, 540, 541, 567). Third, DCs that express maturation markers are not always immunogenic (the maturation concept is reviewed in details in Ref. 430). Tolerogenic DCs are known to express substantial level of costimulatory molecules, and other maturation markers and certain environmental signals seem to mature DCs into a tolerogenic mode. B. Development and Origin of Dendritic Cells Several DC subsets have been identified in both mice and humans. These subsets are distinguished by marker expression, function, location in the body, and whether they are generated in the steady state or during inflammation. Two classes of DCs are present in the steady-state plasmacytoid DCs and conventional DCs (FIGURE 2). Conventional DCs can be further subclassified into migratory and lymphoidresident DCs. The precursor-progeny relationship of monocytes, macrophage, and DCs has been debated ever since the discovery of DCs. There is also a significant difference between mouse and human DC subtypes, which must be taken into consideration. Recent data indicated that both the plasmacytoid and the conventional lymphoid resident DCs derived from a common bone marrow progenitor. A CDP (common DC precursor) was identified from bone marrow that efficiently generated in vitro and in vivo plasmacytoid and conventional DCs but not other cell lineages (372, 393). However, other researchers described that conven- Moreover, it was demonstrated that at least a few subsets of tissue resident DCs (inflammatory DCs) derived from monocytes in vivo (152, 423). In addition human blood monocytes are a commonly used precursors for ex vivo generation of DC (monocyte-derived DC) (452). Consistent with the common origin of macrophages and DCs, several well-established transcription factors, which were considered as a macrophage specific regulator, are also important for DC development. For example, PU.1 transcription factor is required for myeloid DC development (18, 179). Together these results suggested that probably a similar set of transcription factors and signaling pathways shapes the differentiation and function of DCs and macrophages. The molecular details of the regulation of DC differentiation are still poorly characterized, although it was described that several cytokines and transcription factors are necessary for DC development (570, 588). Flt3 ligand is critical for the development of both conventional and plasmacytoid DC differentiation; in contrast, GM-CSF promotes only conventional DC development (570). In addition, in humans, treatment with IL-4 and GM-CSF cytokine is used for the ex vivo generation of monocytederived DCs (452). Much less is known about the transcriptional regulation of DC development, and only a few putative “master” transcription factors have been identified so far (588). Differentiation, lineage development, and also subtype specification is known to be controlled by various cytokines in the case of both macrophages and DCs. However, this process is very much influenced by the extra- and intracellular lipid milieu (FIGURE 1). In the rest of this review, we will summarize what is known about the contribution of lipid-activated transcription factors, nuclear hormone receptors to these processes. Due to the large amount of data Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 747 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 First, recent studies suggest that Langerhans cells are dispensable for T cell priming, and in vivo mouse Langerhans cells appear to suppress the immune responses (151, 246, 259). These data are paradoxical considering that Langerhans cells are featured in many textbooks as prototypical DCs. tional DCs, monocytes (139), and even plasmacytoid DCs (24) share a common progenitor, the MDP (macrophage and DC precursor), suggesting that these cells have a common origin. The ontogenetic relation between MDP and CDP is controversial. These progenitors probably represent different stages of differentiation along the same pathway. Indeed, a recent report suggested that MDPs produced monocytes and CDPs, and CDPs are further restricted to generate conventional DC precursors (pre-cDCs) and plasmacytoid DCs (301). Plasmacytoid DCs are profoundly different from conventional DCs. These cells live longer and harbor characteristic immunoglobulin rearrangements. They can be found in bone marrow, in the blood, and on the periphery and are specialized to respond to viral infection by producing massive amounts of IFN-␥. Plasmacytoid DCs are also involved in antigen presentation and induction of tolerance. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES available, we will restrict our review to receptors heterodimerizing with the RXR. IV. RXR AND ITS PARTNERS: RAR, LXR, PPAR, AND VDR Although many other nuclear receptors [e.g., glucocorticoid receptor (GR) and estrogen receptor (ER)] are also expressed and have documented immunomodulatory role in macrophages and DCs, in this review we will focus on RXR and its partners: RAR, LXR, PPAR␥, and VDR (TABLE 1). We will not cover the potential role of other RXR partners, e.g., Nurr1, PXR, CAR, and PPAR␦/, because they are not expressed in these cells or have not been investigated in sufficient details. In this section we cover the general features (e.g., receptor isotypes, ligands, knockout phenotypes, and general functions) of RXR and its partners, RAR, LXR, PPAR and VDR, while in subsequent sections we review the specific roles for these receptors in macrophages and DCs. Finally, we will 748 A. Retinoic Acid Receptors (RARs and RXRs) Are Activated by Vitamin A Derivatives Vitamin A and its derivatives, retinoids, have profound effects in development, differentiation, homeostasis, and various aspects of metabolism. The discovery of retinoid receptors substantially contributed to the understanding of how these small, lipophilic molecules, most importantly retinoic acid (RA), work as a morphogenic hormone and exert their pleiotropic effects (159, 307, 336, 410). There are two families of retinoid receptors, RARs and RXRs, that are capable of recognizing retinoids specifically and exert their biological effects by regulating gene expression (112). Both families contain three isotypes: ␣, , and ␥ encoded by separate genes and giving rise to numerous alternatively spliced variants (60, 74, 249, 306, 317–319, 584). RARs can be activated by all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA), while RXRs can be activated only by 9-cis RA (200, 292). There are natural and synthetic compounds with at least some selectivity for RXR (33, 49, 283, 292) termed rexinoids (359). RARs have been implicated in embryonic (336), skeletal, (307), and myeloid development (248, 250); in wound healing; in keratinization (172); and also in the developing nervous system (491). RAR␣, RAR, and RAR␥ null mice are viable. They display some aspects of the fetal (and postnatal) vitamin A deficiency (VAD) syndromes (566). For a detailed overview, we refer the reader to a recent review (323). RXR has a unique role among nuclear receptors because it forms heterodimers with other nuclear receptors (60, 287). Therefore, ligand activation has potentially pleiotropic effects on numerous biological pathways and has been implicated not only in retinoid responses but also in various metabolic pathways. RXR was originally identified as a novel retinoid-responsive transcription factor (319). However, it turned out that RAR was more similar to the TR than to RXR, suggesting that these two retinoid receptors are implicated in distinct pathways instead of representing a redundant retinoid signaling pathways. The lack of RXR␣ results in embryonic lethality in homozygous embryos (249, 490). The abnormalities observed in RXR null mice were highly similar to the effects of embryonic VAD (251). One of the most enigmatic areas of the nuclear receptor field is the existence of endogenous RXR activators and Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 The nuclear receptor superfamily includes both steroid and nonsteroid receptors (318). Most of these proteins bind small lipophilic molecules, which either enter the cells or are generated inside the cell (FIGURE 3). One-third of the 48 human nuclear receptors form heterodimers with RXR (78, 154). Among these RXR partners, there are “classical” endocrine receptors, e.g., thyroid hormone receptor (TR), RAR, and VDR, which are activated by high-affinity ligands, such as thyroid hormones, alltrans-retinoic acid, and 1␣,25-dihydroxyvitamin D3 [1,25(OH)2D3], respectively. Another group of RXR partners consists of “adopted orphan” receptors, e.g., LXR, PPAR, and farnesoid X receptor (FXR). These receptors are activated mainly by metabolites, like oxysterols, fatty acids, and bile acids, which bind their receptors with low affinity (318, 473). Most RXR partners require RXR as an obligatory dimerization partner for DNA binding and transcriptional activity (FIGURE 3). As a general principle, RXR heterodimers are believed to reside in the nucleus bound to directly repeated response elements with half site sequence AGGTCA or a variant of it. RXR heterodimers are also believed to repress transcription in the absence of a ligand by recruiting a repressor complex. Upon ligand binding, transcriptional activation takes place as a result of a molecular switch replacing the corepressor complex with coactivator complex(es) (368). In addition, ligand-bound receptors can contribute to gene expression regulation without binding DNA by a phenomenon termed transrepression. In such cases, the receptor interferes with the activity of other transcription factors by protein-protein interactions combined with posttranslational modifications. Most prominently some of the anti-inflammatory activities of various RXR heterodimers are believed to use such pathways (FIGURE 3). discuss the interactions between the various pathways and also how regulated ligand production contributes to lipid signaling in these cell types. NAGY ET AL. Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 FIGURE 3. The principles of ligand generation and nuclear receptor action. A: biologically active ligands of nuclear receptors can be derived from the surrounding environment, from the bloodstream, or can be generated endogenously from their precursors. B: prototypic natural ligands of RXR and its partners are shown. C: active ligand or its precursor enters the cell and gets into the nucleus where it binds the receptor. Precursors go through enzymatic transformation(s). Liganded receptors can recruit coactivator and corepressor complexes to activate or repress transcription, respectively. For gene regulation, RXR heterodimers bind specific DNA sequences, called hormone response elements. Alternatively, nuclear receptors might interfere with the activity of other transcriptional factors, such as NF-B and AP-1. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 749 NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES Due to the fact that RXR works as a general dimerization partner for many nuclear receptors (60, 261, 271, 287), the other intriguing question concerning RXR is if there is a heterodimer-independent RXR signaling. There are in vitro data showing the presence of RXR homodimers and tetramers, but under in vivo circumstances, no RXR homodimer has been detected (84, 257, 542). This is probably due to the strong binding capacity of RXR monomer to its dimerization partners, and until such free partner is present, no RXR-RXR interaction occurs. Our recent gene expression profiling provided some clues though regarding heterodimer-independent RXR signaling in DCs (508). Importantly, RXR seems to be an ancestral nuclear receptor from which many of the other receptor families emerged. Ligand-binding domains of the RXRs from different species show high degree of similarity from jellyfish to human, and all are capable of binding 9-cis RA (268). The more advanced arthropods including the insects have no RXR per se but express ultraspiracle (USP), a homolog of the RXR (195, 396). These suggest that RXR signaling appeared before RAR, PPARs, and LXRs emerged, suggesting the persistence of autonomous RXR signaling. However, it is also possible that evolution generated multiple partners for the RXR, which can act only through its partners today. B. LXRs Are Cholesterol Sensors LXRs are involved in many cholesterol- and bile acid-related biological and pathological processes. LXR␣ and - were cloned in 1994 based on sequence homology with other nuclear receptors from a liver-derived cDNA library. LXR␣ is highly expressed in the liver and at lower levels in adipose tissue, intestine, lung, kidney, the adrenal glands, and macrophages. LXR is ubiquitously expressed (479, 750 565). Three LXR␣ isoforms have been reported so far, all derived from the same gene via alternative splicing and differential promoter usage (80). As far as the regulation of the receptors are concerned, in human but not in mouse cells LXR can induce its own transcription (275, 295, 562). With the study of the promoter of LXR␣, CCAAT/enhancer-binding proteins (C/ EBPs) were reported to isotype and cell-type specifically regulate LXR␣ expression (483). Remarkably, PPAR␥ can also induce the expression of LXR␣ (77). Interestingly, resveratrol, a naturally occurring polyphenol, was also shown to regulate the expression of LXR␣ in human macrophages, which could be a possible molecular explanation for some beneficial effects of polyphenols in cardiovascular diseases (468). LXRs, similarly to PPARs, have large hydrophobic cavities that enable the binding of several different ligands with lower affinity (58, 382, 530). A number of oxysterols have been identified as potential endogenous ligands for LXR. 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 22(R)-hydroxycholesterol, and 24(S),25epoxycholesterol were shown to bind to and activate LXRs at physiological concentrations (231, 284, 404). Several other cholesterol metabolites have been reported recently as potential LXR activators. For a detailed overview of LXR activator oxysterol metabolites, we refer to a recent review (523). The search for endogenous LXR activators placed oxysterol-producing enzymes in the focus of LXR research. One of the candidates, CYP27, is a p450 enzyme that generates 27-hydroxycholesterol, which can activate LXR (148, 230, 231, 498). CYP27 is induced during macrophage development and is a direct target for RAR, RXR, and PPAR␥ receptors (498). Recently, Mitro et al. (339) assigned an unexpected role for LXR, by showing that the receptor could function as a potential glucose sensor and glucose could activate LXRdependent gene expression. However, others reported that glucose is required for the transcription factor carbohydrate-responsive element-binding protein and that LXRs are not necessary for the induction of glucose-regulated genes in liver (120). Therefore, the contribution of glucose to LXR activity requires further studies. There are two widely used synthetic LXR agonists. T0901317 is a nonsteroid LXR activator (435), which also activates farnesoid X receptor (FXR) and pregnane X receptor (PXR) (214, 340). GW3965 is another potent nonsteroid LXR-selective activator (92). These molecules usually do not discriminate between LXR␣ and LXR. However, LXR-selective agonists also exist. N-acylthiadiazolines show increased selectivity for LXR (345). Despite the selectivity and modest potency, the com- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 RXR-specific signaling. Several molecules have been identified as potential endogenous ligands for RXR: 9-cis RA (200), phytanic acid (290), and docosahexaenoic acid (116), but none of these has been proven to be the bona fide endogenous activator so far. Chambon and colleagues (66) excluded 9-cis RA as the RXR ligand during keratinocyte differentiation by using a combination of RAR and RXR conditional knockout mice. Perlmann and colleagues (478) created a ligand detector mouse line. They constructed transgenic lines using Gal-DNA binding domain and RXR-ligand binding domain fusion protein, a reporter gene, -galactosidase containing Gal binding sites in the promoter. X-gal staining of mouse embryos revealed sites of ligand production. Staining of specific regions in the spinal cord suggested the production of endogenous ligand. Luria et al. (310) used a similar system with green fluorescent protein as a reporter (310). They also obtained reporter/RXR activity in spinal cord and upon exogenous ligand treatment in the brain and in the olfactory epithelium. NAGY ET AL. pound still induces cholesterol efflux from macrophages with full efficacy. The major function for LXR is the regulation of lipid metabolism at various levels. Activation of the receptor induces the expression of sterol regulatory element binding protein 1c (SREBP-1c), a central regulator of fatty acid synthesis (117, 434, 462, 579). In addition to SREBP-1c, LXRs regulate several other enzymes involved in lipogenesis such as fatty acid synthase (239), acyl-CoA carboxylase (512), and stearoyl-CoA desaturase 1 (551). When mice were treated with LXR agonists, increased hepatic and plasma triglycerides were observed, generating a serious limitation on the therapeutic introduction of LXR agonists (88, 174, 462). Furthermore, LXR induced genes are involved in the uptake of lipoprotein particles, like low-density lipoprotein receptor (LDLR) (223) and scavenger receptor BI (SR-BI) (315, 582). LXRs also control the expression of members of the ATPbinding cassette (ABC) superfamily of membrane transporters such as ABCG5 and ABCG8 (433, 536) in the intestine or ABCA1 and ABCG1 in macrophages (99, 255, 435, 450, 464). In vivo consequences of LXR activation have also been studied. Administration of a synthetic LXR agonist T0901317 induces expression of LXR target genes, like ABC transporters and lipogenic genes, and results in increased triglyceride and phospholipid levels and in hepatic steatosis in mice (88, 174, 462). The same compound decreased atherosclerotic lesion development in LDL receptor (LDLR) knockout mice (516). Another LXR agonist, GW3965, induced expression of LXR target genes in the small intestine and also in macrophages and increased reverse cholesterol transport by increasing high-density lipoprotein cholesterol concentration (92). Although LXR ligand treatment reduced atherosclerotic lesion size in LDLR and apolipoprotein E (apoE) knockout animals (240), due to their effects on lipogenesis, the potential benefit of LXR activators in the treatment of atherosclerosis is limited (for details, see sect. VIIC). C. PPARs Bind a Broad Range of Fatty Acids and Diverse Synthetic Ligands There are three members of the subfamily of PPAR. PPAR␣ is expressed most prominently in the liver and In this review we focus on one member of the family, PPAR␥, because this has been shown most extensively to act as a modulator of macrophage and DC differentiation and function. The first endogenous ligand for PPAR␥ was suggested to be a prostanoid, 15-deoxy-⌬12,14-prostaglandin J2 (PGJ2) (141, 260, 581). However, the amount of this compound appeared to be too low or nondetectable in tissues for activating PPAR␥ (417). In macrophages it has been shown that molecules from oxLDL can activate PPAR␥. These were identified to be oxidized derivatives of fatty acids, like 9-hydroxyoctadecadienoic acid (HODE) and 13-HODE (325, 371, 461). Recent studies on PPAR␥ ligand binding revealed that it has a relatively large ligand-binding pocket resulting in the possibility that two ligands can simultaneously occupy the pocket (225). Another unique feature of PPAR␥ ligand binding is that oxo and/or nitrated fatty acids can be coupled covalently to the receptor generating a more potent activation than noncovalently bound ligands (225, 296, 544). The essential role of PPAR␥ has been demonstrated in adipocyte differentiation (30, 57, 270, 445, 519), placental development, and vascularization (30, 514, 515). PPAR␥ deficiency results in embryonic lethality. A disturbance in terminal differentiation of trophoblasts and placental vascularization leads to myocardial thinning and death by E10.0 (30). Tetraploid-rescued mutant exhibited another lethal combination of pathologies, including lipodystrophy, fatty liver, and multiple hemorrhages (270, 445). Those PPAR␥ null mice that survived to term were deficient for all forms of adipose tissue providing evidence for the fundamental role of PPAR␥ in adipogenesis (30). In macrophages PPAR ␥ regulates many aspects of lipid/cholesterol metabolism and inflammation, which will be detailed below (77, 371, 437, 520). By coordinating cholesterol uptake and efflux the recep- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 751 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 LXRs do not only regulate the synthesis of lipid molecules, but their target genes are involved in the regulation of lipid transport as well: lipoprotein lipase (LPL) (591), cholesteryl ester transfer protein (309), phospholipid transfer protein (PLTP) (67, 274, 313), apolipoprotein E (276), and the apolipoprotein C-I/C-IV/C-II gene cluster (314). regulates fatty acid oxidation (124). PPAR␥, which is expressed in adipose tissue, macrophages, and DCs, regulates lipid uptake and storage (503, 521) and immune responses. The ubiquitously expressed PPAR/␦ is implicated in fatty acid metabolism, mitochondrial respiration, thermogenesis, muscle lipid metabolism, and fibrotype switching (124). They all bind various nonesterified fatty acids, polyunsaturated fatty acids, eicosanoids, or prostanoids and regulate aspects of lipid metabolism in which there is remarkably little overlap in spite of the fact that they all bind to the same response element. A common feature of PPARs is that they are all targets of drug discovery and have clear therapeutic utility. PPAR␣ and PPAR␥ are the targets of lipid-lowering fibrates (256) and thiazolidinediones (TZDs) used in insulin sensitization (521), respectively. Ligand for PPAR/␦ may be useful in muscle wasting syndromes (376). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES tor is a central player in foam cell formation, one of the earliest steps during atherogenesis. D. VDR Is a Classical Endocrine Receptor According to the IUPAC-IUB, the term vitamin D should be used as a general term to describe all steroids that exhibit qualitatively the biological activity of cholecalciferol or vitamin D3 (1). In this way, vitamin D refers to many members of a group of secosteroids; these molecules have similar structure to steroids, but one of the rings has been broken. The two major physiologically relevant forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is the major naturally occurring form of the vitamin in plants (204). Although vitamin D2 has been shown to contribute significantly to the overall vitamin D status in humans, and metabolized in a similar fashion as vitamin D3 (191, 209), for simplicity here we focus only on vitamin D3 metabolism. Humans get vitamin D3 from exposure to sunlight, from their diet, and from dietary supplements (204). Vitamin D3 can be synthesized in the skin: 7-dehydrocholesterol is converted to pre-vitamin D3 when ultraviolet B (UVB) penetrates the skin. Pre-vitamin D3 is then spontaneusly isomerized to vitamin D3. Vitamin D3 is not found in plants and is present in low abundance in most animal sources, except in fish species, fish liver oil, liver, and eggs (119) which are rich in vitamin D3. Vitamin D3 is a prehormone, and it is activated by two hydroxylation steps (reviewed in Ref. 418). The first step occurs mainly in the liver and converts vitamin D3 to 25-hydroxyvitamin D3 [25(OH)D3]. Circulating 25(OH)D3 is bound to vitamin D binding protein. 25(OH)2D3 is the major circulating form of vitamin D used by clinicians to determine the vitamin D 752 Mice deficient in VDR are viable, but display a phenotype that resembles vitamin D-dependent rickets type II in humans (135, 203, 297, 580). The phenotype includes rickets and osteomalachia, elevated levels of and resistance to 1,25(OH)2D3, hypocalcemia, profound secondary hyperparathyroidism, total alopecia, and abnormal skeletal muscle development. Remarkably, depending on the ablated exons of VDR, there are differences in the phenotype of different VDR⫺/⫺ mice (e.g., in fertility and life span) (297, 580). V. THE BIOLOGY OF RAR AND RXR IN MACROPHAGES AND DENDRITIC CELLS A. Retinoids in Myeloid Development RARs are expressed in nearly all hematopoietic lineages (524) and play critical roles in hematopoiesis (248, 250). In myeloid cells, RAR␣ is the dominant isoform; however, RAR and -␥ are also expressed at a lower level (114, 285). RAR can induce its own transcription (115); however, in myeloid cells the silencing DNA methylation on the promoter of RAR needs to be first erased for RAR to be expressed (125). RAR contributes to myeloid differentiation through regulating expression of its target genes involved in the differentiation program. However, the contribution of RAR to early myeloid development and to the granulocyte lineage is more prominent than to the monocytic development (see below). RAR␣ induces C/EBP⑀ (87, 399, 575), CD18 (12, 63), CD38 (128), RTP801, a recently discovered inhibitor of the mTOR pathway (155), interferon regulatory factor-1 (IRF1) (327), and leukocyte alkaline phosphatase (158) and mediates cell cycle arrest, a key phenomenon during differentiation (477, 545). MCSF, M-CSF receptor, G-CSF, GM-CSF, and GM-CSF receptor were also reported to be induced by retinoic acid in bone marrow stromal cells (111, 216, 373, 552). Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 In contrast to RXR, LXR, and PPAR, the ligand of VDR was discovered before the cloning of the receptor. The nutritional forms of vitamin D were identified, and their sturctures were determined during the 1920s and 1930s (reviewed in Ref. 119). 1,25(OH)2D3 (calcitriol), the active form of vitamin D, was identified and synthesized in the 1970s (143, 205). The existence of the VDR was demonstrated in the 1970s by Brumbaugh et al. (55, 56), while cloning of the cDNA encoding the human and rat VDR was reported in the late 1980s (27, 61, 62). Vitamin D is essential for promoting calcium absorption in the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal mineralization of bone (119). It is also required for bone growth and bone remodeling by osteoblasts and osteoclasts. The classical manifestations of vitamin D deficiency are rickets (in children), osteomalacia, and osteoporosis (in adults) (204). However, a series of experiments demonstrated that VDR is expressed in most tissues in the human body, and vitamin D plays an important role in decreasing the risk of many chronic illnesses, cancers, autoimmune diseases, infectious diseases, and cardiovascular disease (204). status. The second step occurs primarily in the kidney and forms the physiologically active 1,25(OH)2D3. Remarkably, many extrarenal tissues have the capacity to produce the CYP27B1 enzyme responsible for the hydroxylation of 25(OH)D3. The inactivation of vitamin D metabolites is also carried out by a hydroxylation step; CYP24A1 is the key enzyme in 24-hydroxylation. Although nongenomic activity of 1,25(OH)2D3 is also documented, the majority of its effect is thought to be carried out by VDR localized in the nucleus. VDR is a high-affinity hormone receptor and a nonpermissive partner of RXR. Ligand-bound VDR can regulate gene expression via various molecular mechanisms, including direct activation where VDR-RXR most effectively binds DR-3 (direct repeat with 3-bp spacer) response element (528). NAGY ET AL. Nonetheless, retinoids have a dual effect on developing cells, either inducing maturation or cell death depending on the cellular context and presence of other factors. In a murine hematopoietic cell line, ATRA inhibited IL-6induced differentiation by downregulating IL-6 receptor (395). ATRA not only induces myeloid lineage but can also repress erythroid differentiation by downregulating GATA1, a key regulator of erythroid development (272). When blood monocytes were cultured in the presence of GM-CSF and ATRA, DC-like cells were generated in terms of morphology, CD1a expression, adhesion, costimulatory molecule expression, and T-cell activation (342). As far as genetic evidence for the receptors involvement is concerned. RAR␣ and -␥ knockout mice display a block in granulocytic differentiation (236, 273). Dominant negative RAR␣ blocks neutrophil development at the promyelocyte stage (235, 525) and switches normal granulocyte/monocyte differentiation to basophil/mast cell development (524). RAR was reported to act as a differentiation checkpoint switch at the promyelocytic stage of granulopoiesis, resulting in granulocytic differentiation (592). Following induction of myelomonocytic differentiation, induction of RAR␣ was observed (593). Retinoic acid (RA) stimulates the maturation of myeloid precursors in cytokine-stimulated CD34⫹ cells (236). One of the most studied examples of leukemia is acute promyelocytic leukemia (APL). In APL a t(15;17)(q22;q12) chromosome translocation generates a PML-RAR␣ fusion protein that inhibits RAR, resulting in a block of terminal differentiation of granulocytes (236, 241, 553). Promyelocytic leukemia cell lines can be differentiated, and APL patients can be successfully induced into remission with treatment of ATRA (93, 113, 131, 241, 470, 555). The translocation generates a PML-RAR␣ fusion protein, which cannot release histone deacetylase (HDAC) complex at physiological ATRA concentrations leading to the maintenance of repressive chromatin marks and corepressor binding (178, 193, 299). Dissoci- However, the mechanism of PML-RAR␣-induced repression is more complicated. PML-RAR␣ was also shown to interact with PU.1, a master regulator of hematopoiesis, and the interaction results in the suppression of PU.1, which leads to differentiation block (357). ATRA induces degradation of the PML-RAR␣ and restores PU.1 function. The majority of PU.1 binding sites are in close proximity of variably spaced RAR binding sites, which seemed to be prerequisite for subsequent repression (546). Besides the HDACs and PU.1, PML-RAR␣ mistargets many chromatin modifiers resulting in the formation of repressive marks, H3K27me3, H3K9me3, and DNA methylation (68, 125, 537). Despite these new findings, it is still elusive what the crucial determinants for PML-RAR␣ binding to a specific region are. It could be the DNA sequence, chromatin structure, interaction with other transcription factors, or the combination of these. In support of RXR’s involvement, expression of RXR␣ was reported to correlate with the differentiation stage of myelomonocyte cells showing higher levels in more matured cells (118). RXR-specific agonists were shown to overcome the dominant negative effect of mutant RAR␣ and induce myeloid differentiation (235). RXR agonists independently from the RAR could lead to maturation of APL cells via a crosstalk between RXR and protein kinase A (39). A combination of RAR and RXR activators could induce maturation of myeloid cell lines more efficiently than single agonists (470). However, others report that RAR and RXR have distinct functions in myeloid differentiation by inducing either differentiation or apoptosis, respectively (40, 49, 333). Ligand activation of RARs in HL-60 cells resulted in suppression of BCL-2 expression, whereas ligand activation of both RARs and RXRs triggered the selective accumulation of tissue transglutaminase in the apoptotic HL-60 cells (367, 369, 370). RXR was also shown to perturb myeloid differentiation when a dominant negative mutant was expressed in mice (493). Nevertheless, myeloid-specific deletion of RXR␣ had no major consequences on hematopoiesis (439). Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 753 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 There is evidence for crosstalk between nuclear receptor pathways involving RAR. Probably through the induction of C/EBPs RAR can induce PPAR␥ expression and potentiates the effects of PPAR␥ agonists on assisting macrophage development (499). The PPAR␥ target gene CD36, a scavenger receptor on macrophages, is also regulated by RAR (189). While ATRA is a more efficient inducer of granulocytic than monocytic development, vitamin D acts oppositely (32, 127, 266, 518). Vitamin D analogs are widely used to induce monocytic differentiation. Interestingly, a combination of retinoids and vitamin D may be more efficient, suggesting the possibility of a synergistic crosstalk between the two pathways (45, 51, 54, 374). ation of the corepressors NCoR or SMRT from PMLRAR occurs at high doses of ATRA, explaining the biological effect of pharmacological concentrations of RA (178, 180, 193, 299). These results suggest that a failure in HDAC release is the mechanism of APL. This was further supported by the findings on PLZF-RAR fusion protein, which is the result of a t(11:17) translocation (335). Patients with this translocation are resistant to ATRA treatment, since unlike PML-RAR, PLZF-RAR is ATRA insensitive so HDAC and corepressors are not released. Nevertheless, combination of ATRA and HDAC inhibitors can induce relief of repression and admit differentiation. These findings established the role for HDAC inhibitors in clinical therapy (85, 556). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES Therefore, probably due to the extensive combinatorial possibilities of RAR regulation and the promiscuity of RXR, the deconvolution of the exact role of RARs in myeloid cell differentiation is far from over. B. Retinoids in Monocyte/Macrophage Function The mobility of monocytes/macrophages is affected by retinoids. 9-cis RA was shown to induce monocyte chemoattractant protein expression in human monocytic leukemia cells (594). G-CSF and a novel RAR␣-specific agonist, VTP195183, were shown to synergize and enhance the mobilization of hematopoietic progenitor cells from the bone marrow (196). The effect of retinoids on cytokine production is also controversial in the literature. There are pieces of evidence for both a pro- and anti-inflammatory role. The pieces of evidence for an anti-inflamatory role are the following: ATRA was shown to inhibit TNF and nitric oxide production in peritoneal macrophages (334). In addition, ATRA enhanced the production of IL-10 while reduced the synthesis of IL-12 and TNF-␣ in LPSstimulated monocytes/macrophages (549). It was suggested that ATRA repressed IL-12 expression via an interaction between RXR and NF-B (366). Another level of the anti-inflammatory effects of retinoids is the attenuation of tissue damage at the site of inflammation. ATRA could induce plasminogen activator inhibitor-2 production in blood mononuclear cells, which inhibited urokinase-induced extracellular proteolysis (346). In DBA/1J mice with collagen-induced arthritis (CIA), retinoids improved the clinical course of the disease and reduced the production of inflammatory cytokines, immunoglobulin, and chemokines MCP-1, IL-6, IL-12, TNF, total IgG, and IgG1 anti-collagen antibodies (384). In a rat model of chronic allograft nephropathy, 13-cis RA treatment decreased the number of infiltrating mononuclear cells, their proliferative activity, and synthesis of MCP-1, MIP-1␣, IP-10, RANTES, plasminogen activator inhibitor-1, transforming growth factor-1 (TGF-1), and collagens I and III (3). 754 There are also pieces of evidence to support a more proinflammatory and enhanced antimicrobial response. In a randomized study on rats treated with RA, the severity of tuberculosis infection was attenuated by increasing the numbers of T cells, natural killer cells, and macrophages in the lung and spleen, and the levels of IFN-␥, TNF, IL-1, and iNOS were higher (573). RAR␥-deficient macrophages exhibited impaired inflammatory cytokine production upon TLR stimulation and defective immune response to Listeria monocytogenes (132). Clearly, a more systematic analysis of RARs contribution to inflammatory paradigms needs to be carried out. C. Retinoids in Macrophage Metabolism The role of retinoids in macrophage metabolism is still largely unexplored. A link between RAR, PPAR, and LXR signaling is that CYP27, a mitochondrial P-450 enzyme capable of generating 27-hydroxycholesterol, is under complex regulation by RAR, RXR, and PPAR␥ (498). The oxidized cholesterol derivative product of CYP27 could activate LXR to induce cholesterol efflux from foam cells, thereby contributing to cholesterol removal from vessel wall and reverse cholesterol transport (148, 231, 498). Costet et al. (98) reported that the RAR␥:RXR heterodimer induced the expression of ABCA1 in macrophages. In in vivo studies, ATRA suppressed lesion development induced by Chlamydia pneumoniae in hyperlipidemic C57BL/6J mice while had no effect in uninfected animals (234). The synthetic retinoid AM580 suppressed scavenger receptor expression and macrophage foam cell formation in vitro and prevented atherogenesis in apoE-deficient mice in vivo (510). In carbohydrate metabolism, ATRA induces aldose1-epimerase (mutarotase), which catalyzes the interconversion of ␣ and  hexoses, essential for normal carbohydrate metabolism and the production of complex oligosaccharides. Through this pathway retinoids could affect energy utilization and synthesis of cell-surface glycoproteins or glycolipids involved in cell motility, adhesion, and/or functional properties (398). Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 The availability of natural and synthetic ligands for RAR and RXR made it possible to generate a vast array of data regarding monocyte/macrophage function. However, only a fraction of these findings have been ascribed to receptor activation using more extensive pharmacological and/or genetic approaches. Therefore, it is quite possible that some of the effects are not receptor-dependent or do not require the receptor’s genomic activity. In a model of lupus nephritis in MRL/lpr mice, ATRA reduced lymphoadenopathy and splenomegaly and proteinuria. Although plasma IgG and anti-DNA antibody levels and immunocomplex and complement deposition were not affected, the numbers of infiltrating T cells and macrophages were decreased. Simultaneously, renal TGF- level was elevated (409). Similar results were obtained when rat glomerulonephritis models were used (286, 457, 458). Both liposomal and free ATRA could decrease the expression of matrix metalloproteinase-9 (MMP-9) and induce its inhibitor, tissue inhibitor of matrix metalloproteinase 1 (TIMP1), in bronchoalveolar lavage cells (142). NAGY ET AL. D. Effects of Retinoic Acid on DC Function There is limited information about the expression of RARs in DCs; however, a few studies indicated that at least some of the isotypes of RAR and RXR proteins can be detected in DCs. Consistent with these results, Geissmann et al. (153) described that in the presence of pro-inflammatory stimuli ATRA further enhanced the maturation of DCs; moreover, it was suggested that the NF-B activation was responsible for this effect. However, without inflammatory stimulation, ATRA treatment itself elicited programmed cell death in this DC model (153). Our data also indicated that synthetic retinoid-treated DCs regulate a large number of genes and pathways. For example, retinoid signaling coordinately regulated the CD1 gene family expression. Group 1 CD1 genes (CD1a, CD1b, CD1c, and CD1e) were downregulated, whilst group 2 CD1 (CD1d) was upregulated upon ATRA treatment (504). Furthermore, our analysis revealed that the enhanced expression of CD1d leads to an elevated natural killer T-cell activation capacity of these cells. We will further discuss the CD1 gene family regulation on section VIIF. Taken together, these observations suggested that activation of RAR positively modulates the immunogenicity of DCs. It is well known that retinoid signaling had an important role for polarization of lymphocyte development (see sect. XB); however, as we have described here, ATRA could also instruct DCs, and this might also contribute for induction of oral tolerance and regulation of the immune response. However, other studies reported an opposite effect on RAR activation. An early in vitro study revealed that even low concentrations of ATRA exerted an inhibitory effect on spleen-derived mouse DCs because these cells had an impaired T-cell stimulatory capacity (35). In line with this finding, ATRA inhibited in vitro differentiation and maturation of DCs developed from human cord blood monocytes with impaired IL-12 and increased IL-10 production (513). A recent report also indicated that ATRA-instructed DCs had impaired IL-12 production; moreover, ATRA in vivo might contribute to the IL-12 hypoproductive DC development (543). One study suggested that ex vivo ATRA treatment also confers regulatory T cell inducing capacity of We would like to note here that the role of LXR and PPAR␥ in macrophage lipid metabolism will be discussed in detail in section VIIC. VI. THE BIOLOGY OF LXR IN MACROPHAGES AND DENDRITIC CELLS A. Contribution of LXRs to Macrophage Biology The role for LXR in macrophages appears to be focused to three broad areas: complex regulation of basic lipid metabolism, modulation of immune responses, and the inhibition of apoptotic pathways (FIGURE 4A). LXR activity is modulated by the innate immune system, and vice versa, LXR itself can modify cellular immune responses. A key observation showed that mice lacking LXR␣ were highly susceptible to Gram-positive intracellular pathogen, Listeria monocytogenes infection (237). Bone marrow transplantation experiments revealed that expression of LXRs in hematopoietic cells is required for this effect. An important crosstalk between LXR and TLR signaling was uncovered in cultured macrophages as well as in Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 755 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 In human monocyte-derived DCs, RAR␣ and RXR␣ showed the highest expression, and proteins of these receptors were also detected (504). Notably, mouse splenic DCs expressed all RAR isoforms (320). These results suggest that ATRA can exert a receptor-dependent effect on DCs. Before the discovery of ATRA production by intestinal DCs, the effects of retinoids on DC had already been investigated in detail. An early report indicated that in vivo administration of retinol-acetate or 13-cis RA increased the number of DCs and macrophages in spleen; moreover, these cells had an enhanced immunological function (252), suggesting that retinoid signaling had a positive effect on the immunogenicity of DCs. A human study also indicated that local treatment of ATRA on skin promotes the epidermal DC (Langerhans cells) activation because these cells had an enhanced HLA-DR, CD11c, and CD1c expression (338). DCs (455). ATRA-treated swine monocyte-derived DCs produce more TGF- and IL-6; in addition, these authors proposed that these cells could store and release ATRA, and this retinoid signal also contributed for polarization of Tcell development (455). In mouse splenic DCs, zymosan plus retinol treatment turned on endogenous ATRA production, and it was suggested that the endogenous ATRA acted in an autocrine manner to suppress the production of pro-inflammatory cytokines (IL-6, IL-12, and TNF-␣) (320). Importantly, in this report, the authors started to explore the potential mechanisms of this anti-inflammatory effect. ATRA production stimulated the expression of SOCS3, and the induction of this repressor protein contributed to the anti-inflammatory effects; moreover, ATRA signaling attenuated the activation of p38 MAP kinase (320) (FIGURE 5). It is still controversial how DC migration is regulated by retinoid signaling. One report suggested that murine bone marrow-derived DCs have enhanced migratory capacity upon ATRA treatment in vivo via the enhanced production of MMP-12 (109). However, it was also described that 9-cis RA or a synthetic retinoid negatively regulated the migration capacity of DCs via the downregulation of CCR7 and CXCR4 chemokine receptors (539). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES aortic tissue in vivo by showing that microbial compounds via TLR3 and TLR4 can inhibit LXR target gene expression and cholesterol efflux in an IFN regulatory factor 3-dependent (IRF3) manner (72). LXR was also reported to exert anti-inflammatory effects by inhibiting the expression of several proinflammatory molecules such as iNOS, cyclooxygenase (COX)-2, IL-6, IL-1, MCP-1, MCP-3, and MMP-9 in response to bacterial infection or LPS stimulation (71, 238). Therefore, LXR antagonizes inflammatory gene expression downstream of TLR4 and also IL-1 and TNF-␣-mediated signaling. On the more mechanistic front, 756 Glass and colleagues (157) demonstrated that a similar mechanism of transrepression exists for LXR as reported previously for PPAR␥ ligand binding results in SUMOylation of the receptor, which is recruited to the promoters of inflammatory genes and inhibits LPS-induced corepressor (NCoR) clearance. However, similar unresolved issues exist in connection of this model as in the case of PPAR␥ (see below). This would all point into the direction of LXR being exclusively anti-inflammatory. However, an interesting observation was reported by Fontaine et al. while showing that short-term pretreatment by LXR agonists reduced Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 FIGURE 4. The complex roles of nuclear receptors in macrophages. A: activation of LXR leads to cholesterol efflux by increased removal and decreased uptake, inhibition of apoptosis, and attenuation of inflammatory gene expression. B: PPAR␥ agonists increase cholesterol uptake via scavenger receptors, induce the LXR pathway, and inhibit the inflammatory gene expression. C: two distinct activation mechanisms of macrophages. Exposure to interferon (IFN)-␥ and tumor necrosis factor (TNF) leads to classical activation, whilst interleukin (IL)-4 and/or IL-13 lead to alternative activation. STAT6 facilitates PPAR␥-regulated gene expression changes in macrophages and DCs. D: activation of TLR1/2 heterodimer by Mycobacterium tuberculosis results in the upregulation of VDR and CYP27B1 enzyme. The accumulating 1,25(OH)2D3 activates VDR leading to the induction of cathelicidin and defensin beta 4 genes. The induction of defensin beta 4 requires convergence of the VDR pathway and IL-1 signaling (not indicated). In human macrophages, vitamin D-mediated induction of these antimicrobial peptides seems to be essential in combating Mycobacterium tuberculosis. 1,25(OH)2D3 regulates many other pathways in monocytes/macrophages. For simplicity, these are not indicated. NAGY ET AL. the inflammatory response induced by LPS; long-term pretreatment, however, resulting in an enhanced LPS response (140) suggested that the crosstalk between LXR and TLR signaling is more complex and likely to be context dependent. A difference exists in DCs as well regarding human vs. mouse cells (see below). Moreover, LXR␣ conferred the most protection and the loss of this receptor correlated with macrophage apoptosis. As a potential mechanism, Joseph et al. (237) identified AIM (also known as SP␣, API6, and CD5L), a gene that promotes macrophage survival, as a target of LXR␣ in mouse macrophages. AIM also protects macrophages from apoptosis when exposed to oxLDL, suggesting a role for LXR as a macrophage survival factor during the development of atherosclerosis (237). Valledor et al. (531) reported similar results by showing the upregulation of antiapoptotic factors such as Bcl-XL and Birc1a and the inhibition of proapoptotic elements such as caspases 1, 4/11, 7, 12, Fas ligand, and DNase 1l3 by LXR (531). B. LXR and DC Biology Expression data suggested that LXR is also expressed in DCs. Initially it has been established that LXR␣ is the dominant isoform in differentiating human DCs (156). Furthermore, it was also shown that LPS-induced maturation of DCs is impaired together with some in vitro adhesion properties. This phenomenon was explained by the LXR-dependent regulation of actin-bundling protein fascin (156). Interestingly, recent studies also showed that endogenous LXR ligands are produced by tumors. In turn, these compounds activate LXR and control the migratory capacity of DCs to the tumor tissues in murine models. Downregulated CCR7 expression was suggested as an explanation for this effect. This finding suggests that LXR is being exploited by tumors to support growth (538). However, there are striking differences between human and mouse DCs. VII. THE BIOLOGY OF PPAR␥ IN MACROPHAGES AND DENDRITIC CELLS A. PPAR␥ in Myeloid Development PPAR␥ was shown to influence myeloid development (371, 499, 520). Activation of the receptor by natural or synthetic agonists results in elevated expression of monocytic/macrophage markers such as CD14, CD36, CD11b, CD11c, and CD18 on myeloid leukemia cells. PPAR␥ seems to regulate later stages of the development favoring monocytic development; in addition, expression of the receptor correlates with the developmental stage within the monocytic lineage with highest level in the macrophages (499). Several groups succeeded to differentiate macrophages from PPAR␥-deficient embryonic stem cells, indicating that PPAR␥ is dispensable for monocytic differentiation (76, 347). Its function is rather a modulator of the immune and metabolic functions of the macrophages. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 757 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Most recently, the Castrillo and Tontonoz laboratories jointly demonstrated that LXR is involved in apoptotic cell clearance (365). Macrophages play a role in the elimination of apoptotic cells generated by the billions every day. The uptake is a complex and not well understood process involving “find me” and “eat me” signals (424). Phagocytosis of apoptotic cells by macrophages is significantly enhanced upon LXR ligand addition and LXR-deficient macrophages have a decreased capacity to take up apoptotic cells. Apparently, the lack of the apoptotic cell receptor Mer is responsible for some of these effects, which is identified as an LXR target gene. In addition, LXR has been shown to directly regulate RAR (425), and via this some additional factors got implicated such as the retinoid-regulated enzyme, tissue transglutaminase which has been linked to apoptotic cell clearance (367, 509). Defective apoptotic cell uptake can lead to chronic inflammatory conditions and autoimmune diseases. Our comprehensive analysis of LXR expression and activation provided further details on how activation of LXR induces a differentiation program that effects the response and phenotype of human DCs (522). This program includes induction of costimulatory molecules, increases in proinflammatory cytokine production, and increases T-cell activation (FIGURE 5). Circulating blood CD1c⫹ DCs also responded to LXR ligand treatment, resulting in the increased expression of LXR target genes. DCs similarly to other professional APCs (antigen presenting cells) display a broad array of TLRs to detect a wide array of pathogenic or damaged self structures. In principle, this results in activation of NF-B signaling (226, 431). Importantly, other sensory mechanisms are likely to participate in signal modulation. While LPS interferes with LXR signaling in macrophages by inhibiting the expression of its target genes (72, 238), it appears that in DCs LPS increases the expression of target genes. This suggests that LXR signaling is integrated in the TLR signaling pathway by a context- and cell type-specific manner. It is possible that DCs induce an increased LXR response when exposed to specific TLR activators, provided a ligand is available. This might be a hint about the existence of a potential mechanism for pathogene elimination by an enhanced inflammatory response. The source and origin of such ligand(s) are unknown yet. However, the fact that the production of LXR activating lipids from tumors could be detected (538) suggests that the inflammatory environment has a role in determining the receptor’s activity also in vivo. If put together, the data obtained in macrophages and DCs strongly suggest the existence of an intriguing and so far largely unexplored crosstalk between TLR and LXR signaling. This also means that LXR activation may blunt or enhance host defense depending on the context. How cellular or immune context influences this crosstalk remains to be determined. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 758 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org NAGY ET AL. B. Anti-inflammatory Role of PPAR␥ in Monocyte/Macrophage Although several potential mechanisms for the anti-inflammatory function have been assigned, the exact mechanism is still elusive. The most accepted theory suggests that PPAR␥ agonists interfere with other transcription factors involved in pro-inflammatory signal transduction pathways, such as AP-1, STAT-1, NF-B, and NFAT. This mechanism requires a physical interaction between PPAR␥ and the other transcription factor and subsequent inhibition, a process called transrepression (402, 436). Transrepression is clearly different from the canonical action of nuclear receptors, when they bind to cognate DNA sequences and induce or repress their target genes directly. The molecular mechanism of transrepression is poorly defined; however, it was suggested that there is a ligand-dependent SUMOylation of PPAR␥ that targets the receptor to corepressor complexes on inflammatory genes’ promoters. This prevents the ubiquitination/proteasome-mediated degradation of repressor We recently showed that PPAR␥ is dispensable for alternative macrophage activation per se and IL-4-induced gene expression regulation; however, we found that IL-4 and its effector transcription factor STAT6 is required for PPAR␥ activity in alternatively activated macrophages. We suggested an interesting mechanism for the crosstalk between PPAR␥ and STAT6 by showing that STAT6 acts as a licensing factor for PPAR␥. STAT6 physically interacts with PPAR␥ by binding the enhancers of PPAR target genes and induces PPAR␥-mediated transcription (497). FIGURE 5. Molecular events regulated by nuclear receptor ligands alter the antigen presenting function of dendritic cells. Events leading to altered lymphocyte activation are depicted. Note that many genes regulated similarly in macrophages and DCs are not indicated. A: TLR2 signaling induces splenic DCs to express retinoic acid metabolizing enzymes and IL-10 and stimulate Tregs. All-trans-retinoic acid (ATRA) induces suppressor of cytokine signaling-3 expression (SOCS3), which suppresses the activation of p38 and proinflammatory cytokines (for details see text). B: the upregulation of Cd1d by RAR agonists leads to an enhanced iNKT cell expansion. PPAR␥ can turn ATRA by inducing the expression of retinol and retinal metabolizing enzymes. Therefore, the effects of PPAR␥ and RAR agonists are similar in many aspects. The upregulation of cathepsin D (CatD) lysosomal protease and CD1d leads to an altered lipid antigen presention and enhanced iNKT cell expansion. CD1d is regulated by RAR, while CatD is regulated by both RAR and PPAR␥ in human monocyte-derived DCs. C: DCs reprogrammed with LXR agonist have an increased response to TLR signaling and an augmented cytokine response resulting in proinflammatory T-cell responses. D: activation of VDR leads to a tolerogenic DC phenotype, characterized by decreased expression of CD40, CD80, and CD86 costimulatory molecules, low IL-12, and enhanced IL-10 and CCL22 secretion. The expression of antigen-presenting molecules is also lower, while the level of inhibitory receptors, such as ILT3, is elevated. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 759 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 When PPAR␥ was identified in mouse thioglycolate-elicited macrophages, its activators were shown to exert potent anti-inflammatory effects (437). Originally, they were shown to inhibit macrophage responses to pro-inflammatory stimuli such as LPS or IFN-␥. Natural and synthetic PPAR␥ activators were shown to inhibit production of pro-inflammatory molecules, such as iNOS, MMP-9, and SR-A (437). Similar effects were reported from human monocyte-derived macrophages (233), which led to the conclusion that PPAR␥ agonists may act as potential anti-inflammatory drugs. Over the last 10 years, PPAR␥ agonists have been shown to exert anti-inflammatory effects at multiple levels. For example, PPAR␥ agonists were shown to inhibit the production of many proinflammatory cytokines like TNF, IL-6, IL-1, IL-12, and gelatinase B (17, 89, 233, 293, 437, 438, 489, 561). Furthermore, PPAR␥ inhibits macrophage migration and recruitment by repressing the transcription of chemoattractant molecules such as MCP-1 and its receptor CCR2 (25, 31, 82, 188, 469). PPAR␥ agonists can also induce the production of an anti-inflammatory cytokine, IL-10 (258). Moreover, PPAR␥ suppresses TGF- production indirectly by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (280, 281). complexes, which are required for gene expression (401). This model, however, does not explain how ligand-bound PPAR␥ can exert two opposite reactions simultaneously: dissociation of the corepressor complex from the receptor to induce target gene expression and recruitment of the receptor to corepressor complexes associated with other transcription factors to inhibit proinflammatory gene expression. Importantly, the negative regulatory role assigned to PPAR␥ is not a direct transcriptional effect of the receptor but the consequence of the failed induction of inflammatory genes by other transcription factors activated upon proinflammatory molecules, e.g., LPS (293, 402). Key in vivo genetic evidence is still lacking to support this scenario. Another possible mechanism is the sequestration of essential coactivators when their levels are limiting. Activation of PPAR␥ upregulates PTEN, which inhibits phosphatidylinositol 3-kinase-mediated signaling cascades affecting cell migration, survival, and proliferation, providing a further possibility for suppression of inhibitory reaction (403). Another intriguing possibility to exert anti-inflammatory roles comes from the link between PPAR␥ and the anti-inflammatory cytokine IL-4. Initially, Glass and colleagues (217) showed that IL-4 induced PPAR␥ and an enzyme, 12/15lipoxygenese, capable of ligand production. However, the amount of this compound (15d-PGJ2) appeared to be low in tissues for activating PPAR␥ (417). Recently, Odegaard et al. (387) reported that disruption of PPAR␥ in myeloid cells resulted in impaired alternative macrophage activation and claimed PPAR␥ to be requisite for the differentiation of alternatively activated macrophages. This might not be generally applicable, because in another mouse strain, the receptor appeared to be dispensable (322). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES Remarkably, when the transcriptomes of macrophages were analyzed with DNA microarrays, only a surprisingly small number of regulated genes were found upon PPAR␥ activation (561). The question of macrophage PPAR␥ response has been addressed recently by us showing the requirement of IL-4 and STAT6 for the induction of PPAR␥ target genes (497). PPAR␥ and/or its activators have been implicated in several studies on inflammatory diseases. Several human diseases and mouse models have been analyzed so far, and PPAR␥ agonists were tested whether they inhibit disease progression. Here, without going into the details, we refer to a previous review where we summarized the effects of PPAR␥ activators in airway and intestinal inflammation, autoimmune encephalomyelitis, myocarditis, arthritis, and dermatitis (500). For a more detailed overview of PPAR␥ in airway inflammation, we refer to earlier reviews by others (467, 481, 554). Little evidence has been provided that these effects are really PPAR␥-dependent and not nonspecific consequences of the agonists. PPAR␥ knockout models have not been widely involved in such studies, and the mechanisms of the antiinflammatory effects have also not been addressed in sufficient depth. However, there are a few reports on PPAR␥deficient animals. PPAR␥-deficient heterozygous mice displayed enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis (123). 5-Aminosalicylic acid (5-ASA), an anti-inflammatory drug widely used in the treatment of inflammatory bowel disease, had beneficial effects on colitis only in wild-type but not in PPAR␥ heterozygous mice. It was shown that 5-ASA binds to and activates PPAR␥ and exerts its anti-inflammatory effects through the receptor (446). Targeted disruption of PPAR␥ in 760 macrophages (469) or colon epithelial cells (2) increased susceptibility of mice to dextran sodium sulfate-induced colitis. C. Atherosclerosis: Role of LXR and PPAR␥ in Macrophage Metabolism As detailed above, several lines of evidence support a central role for macrophage-mediated inflammation in the pathogenesis of metabolic diseases. Macrophage infiltration and the formation of foam cells is a prominent feature during atherogenesis (FIGURE 6). Recently, both proinflammatory classically activated and anti-inflammatory alternatively activated macrophages were shown to be present in fatty streaks (52). PPAR␥ was shown to be expressed in lesion macrophages (437, 520), and now a weak correlation was found between the expression of PPAR␥ and alternative macrophage markers (52). However, further studies are required to clarify the effect of inflammatory milieu on macrophages and PPAR␥ activity in the progression of the atherosclerotic plaque. The function of PPAR␥ in foam cells has been characterized in detail. PPAR␥ expression in macrophages could be further increased with oxLDL (371). PPAR␥ had a key role in the regulation of oxLDL uptake into macrophages/foam cells by inducing its direct target gene, the scavenger receptor CD36. Two components from the lipids in oxLDL, 9-HODE and 13-HODE, were identified as endogen activators and bona fide ligands of PPAR␥ (225, 371). These results suggested the following model: macrophages internalize modified or oxLDL via scavenger receptors (e.g., CD36), which unlike LDL receptor are not downregulated by high intracellular cholesterol levels. On the contrary, oxLDL can further increase the expression of CD36 by providing ligands for PPAR␥ and via this positive feedback potentiates its own uptake. Oxidative modification of the LDL particle endows it with the ability to bind scavenger receptors and at the same time converts a component of the particle, linoleic acid, into an effective activator of PPAR␥, 9- and 13-HODE. OxLDL also induces SR-A expression via a PPAR␥-independent way. This regulatory circuit was termed gammacycle and suggested a novel mechanism how oxLDL contributed to foam cell formation and atherosclerosis. These findings suggested the existence of a vicious cycle (positive-feedback loop) leading to atherosclerosis and assigned PPAR␥ a potential pro-atherogenic role. However, synthetic agonists of PPAR␥, the TZDs, are used in treatment of type II diabetes. To dissect the in vivo contribution of PPAR␥ to the process of atherosclerosis, Chawla et al. (77) generated mice lacking PPAR␥ in the macrophages. Due to the fact that PPAR␥ total knockout is embryonic lethal, chimeric mice were used for bone marrow transplantation into irradiated animals. Transplantation of PPAR␥ null bone marrow into LDL recep- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 It is worth mentioning that PPAR␥ agonists can exert receptor-independent effects as shown when PPAR␥ knockout embryonic stem cells were differentiated to macrophages, which still elicited anti-inflammatory reactions in response to PPAR␥ agonists (76, 347). Welch et al. (561) also found that PPAR␥ macrophage-specific conditional knockout mice still show anti-inflammatory effects upon treatment with PPAR␥ activators. They suggested that some of these effects could go through another nuclear receptor, PPAR␦, since at high concentrations PPAR␥ agonists can activate PPAR␦ as well (561). It was also reported that 15d-PGJ2 can repress NF-B activity PPAR␥-independently via inhibiting IB kinase and/or by alkylating p50 – 65 NF-B heterodimers (70, 489). Another PPAR␥independent mechanism involves the induction of suppressor of cytokine signaling (SOCS) 1 and 3, which results in reduced phosphorylation of STAT1, STAT3, Janus kinase 1 (JAK1), and JAK2 in activated astrocytes and microglia (232, 400). NAGY ET AL. proliferation tor knockout animals resulted in significant increase of the atherosclerotic lesion size. Additionally, Glass and co-workers (293) reported that TZDs inhibited the development of atherosclerosis in LDL receptor-deficient male mice. Similar results were shown by Z. Chen and colleagues in apoE knockout mice, another murine atherosclerosis model (83). Targeted disruption of the PPAR␥ gene from macrophages resulted in reduced total plasma and HDL cholesterol levels, and cholesterol efflux was significantly decreased from macrophages elicited by thioglycolate in mutant mice (14). Based on these observations, PPAR␥ can be considered an anti-atherogenic molecule (FIG. 6). Seeking the molecular mechanism assigned a central role for PPAR␥ and LXR in regulating cholesterol uptake and efflux during foam cell formation. These generated a contradiction to the previous observations on PPAR␥-induced oxLDL uptake. This was resolved by showing that activation of PPAR␥ not only results in cholesterol uptake, but it can also increase cho- lesterol efflux from the macrophages. It was shown that PPAR␥ could directly induce transcription of the oxysterol receptor LXR (77). PPAR␥ induces ABCA1, ABCG1 expression, and cholesterol removal from macrophages through a transcriptional cascade via LXR␣. The promoter of the ABCA1 gene was analyzed and while LXR:RXR could activate it, PPAR␥:RXR heterodimer could not (77). They compared PPAR␥- and LXR-induced cholesterol efflux and found that agonists of both nuclear receptors induced cholesterol efflux, and the combination of the ligands was additive. ABCA1 and ABCG1 are members of the ATP-binding cassette family of transporter proteins and are highly expressed in lipidloaded macrophages (536). Mutations in ABCA1 gene result in Tangier disease, a disease characterized by marked cholesterol accumulation in macrophages and impaired cholesterol efflux from fibroblasts (48, 53, 449). Several studies reported that LXRs mediate cholesterol efflux by inducing cholesterol transporters ABCA1, Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 761 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 FIGURE 6. Cellular events of early atherosclerotic lesions. A cross section of an atherosclerotic lesion is depicted. Due to chemoattraction and activation signals, monocytes transmigrate from the lumen to the subendothelial space and become macrophages. They acquire the capacity to take up modified lipoproteins such as oxidized low-density lipoprotein (oxLDL) via scavenger receptors such as SR-A and CD36. Lipid uptake leads to foam cell formation and eventually to the development of a fatty streak. Foam cells have the capacity to eliminate cholesterol via ABC transporters (i.e., ABCA1) toward high-density lipoprotein (HDL) and also to produce cytokines and contribute to further inflammatory reactions. Inset shows the cross section of an artery with an atherosclerotic plaque. The effects of liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are indicated on the figure (for details, see text). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 762 this system results in cholesterol accumulation and contributes to atherosclerosis. D. Role of Myeloid Cell PPAR␥ in Insulin Resistance and Obesity Recently, inflammation and inflammatory cells have been described to be key regulators not only in atherosclerosis, but also in obesity and insulin resistance (212). Due to the fact that macrophages are located throughout the body including interfaces, they provide a potential role in the interplay between metabolic and inflammatory processes. Chronic inflammation is now considered as a general phenomenon in obesity and diabetes mellitus. Infiltration of adipose tissue with classically activated macrophages has been recently described in obese conditions (243, 244, 472, 560, 571). However, the presence of alternatively activated macrophages in adipose tissue and liver reduces tissue inflammation, increases oxidative metabolism, and improves insulin resistance in obese mice (386). It was suggested that overnutrition leads to the recruitment of inflammatory macrophages to the adipose tissue, changing its original alternatively activated phenotype to classically activated one. This then further promotes obesity and leads to insulin resistance. As reported by Odegaard et al. (387), macrophage-specific PPAR␥ knockout mice were predisposed to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, they reported the downregulation of genes in oxidative phosphorylation in both skeletal muscle and liver, which led to decreased insulin sensitivity in these tissues (387). Hevener et al. (197) reported similar results: macrophage-specific PPAR␥ knockout animals have glucose intolerance and insulin resistance in the skeletal muscle and liver accompanied by increased expression of inflammatory mediators. Although these reports suggest important roles for macrophages in the development of insulin resistance and obesity, they cannot be generally applicable, since Marathe et al. (322) found PPAR␥, -␦, and LXRs dispensable for alternative activation and also their loss in macrophages did not exert major effects on obesity or glucose tolerance. Similarly, rosiglitazone improved glucose tolerance in mice lacking macrophage PPAR␥, suggesting that other cell types than macrophages are the primary mediators of the antidiabetic effects of PPAR␥ agonists (322). E. PPAR␥ Expression in DCs IL-4 is an important factor for the alternative activation of macrophages; moreover, this cytokine positively regulates PPAR␥ expression in macrophages (217). Interestingly, IL-4 is a frequently used cytokine for the ex vivo generation of human DCs from peripheral blood monocytes (452). Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 ABCG1, and later ABCG5 and ABCG8 (99, 435, 535, 536). Cholesterol efflux from macrophages is likely to be anti-atherogenic. By showing that LXR␣ is a direct target gene of PPAR␥, activators of PPAR␥ were considered as inducers of LXR-dependent cholesterol efflux. In this modified gamma cycle, activation of PPAR␥ results in the expression and activation of LXR, which in turn induces ABC transporter expression and leads to cholesterol efflux from macrophages. However, the function of such cycle depends on the presence of endogenous LXR activators. Since both PPAR␥ and LXR could be activated by lipid components of oxLDL, it was hypothesized that these nuclear receptors composed a transcriptional cascade that regulated macrophage response to oxLDL (275). The fact that LXR is activated in macrophages exposed to acetylated LDL (275), which is not supposed to contain oxidized cholesterols, suggests the existence of alternative ways to activate LXR. LXR:RXR heterodimers were originally identified as mediators of an alternative retinoid signaling pathway (564, 565) showing that LXR:RXR heterodimer is highly permissive and can be activated from either the RXR side by retinoids or the LXR side by oxysterols (435). Due to the fact that PPAR␥:RXR heterodimer is also permissive, one obvious possibility for the dual activation of the two dimers evokes from the RXR side. The other possible mechanism is the generation of an LXR agonist. A number of oxysterols were identified as potential endogenous ligands for LXR (230, 231, 284, 404). As Szanto et al. (498) showed, both mechanisms are utilized in the macrophages. Retinoids via RAR and RXR and oxidized lipids via PPAR␥ can induce the transcription of a p450 enzyme, CYP27, which generates 27-hydroxycholesterol, an endogenous LXR activator (498) (see above). CYP27 is a mitochondrial enzyme involved in the alternative bile acid synthesis pathway (19, 65, 414, 447, 448) and is expressed in addition to the liver in the lung and also in macrophages (26, 46). It has been also associated with atherosclerotic lesions (102, 219). A mutation in the enzyme results in a rare sterol storage disease, cerebrotendinous xanthomatosis, characterized by xanthomas in tendons and also in the CNS leading to ataxia, spinal cord paresis, neurological dysfunctions, normolipidemic xanthomatosis, and accelerated atherosclerosis (47, 64, 341). Taken together, oxLDL not only provides ligand for PPAR␥ activation, but PPAR␥ also induces LXR function via two mechanisms: 1) it induces the receptor and 2) it induces an enzyme that generates ligand for it. A recent discovery of LXR regulation of Inducible Degrader of LDL receptor (Idol) further reinforces the notion that activation of LXR leads to increased efflux by also inhibiting further uptake (587). The consequence of the uncovered network is increased cholesterol turnover in the macrophages with induction of reverse cholesterol transport. Any disturbance in the activity of the participants or overload of NAGY ET AL. RXR␣, the dimerization partner for PPARs, was detected in monocyte-derived DCs (504), and it was reported that RXR agonist 9-cis RA has a similar phenotype as PPAR␥-specific ligands (585), suggesting the PPAR␥:RXR heterodimer can be activated from both sides of the heterodimer. Taken together, these observations revealed that various subsets of DCs expressed PPAR␥, suggesting a role in modulation of differentiation and/or activation of DCs. F. Modulation of the Immunogenicity and Lipid Metabolism of DCs by Activation of PPAR␥ PPAR␥ can be activated with synthetic PPAR␥ agonists in DCs (for example, with rosiglitazone or troglitazone) as shown by the induction of several generic PPAR␥ target genes (CD36, FABP4/aP2) after ligand administration (502, 503). Much effort has been applied over the past few years to characterize the effects of the activation of PPAR␥ in DCs. Most of these studies investigated the immune function of DCs by assessing their cell surface phenotype, cytokine production, and T-cell activation capacity. First, it was suggested that PPAR␥ activation did not change the immunogenicity (T-cell activation capacity) of murine splenic DCs, although these cells had impaired IL-12 production (137). A similar finding was obtained when the same investigators studied the effects of PPAR␥ ligand on human monocyte-derived DCs. PPAR␥ agonist-treated DCs had impaired IL-12 production; moreover, expression of IP-10 and RANTES chemokines were also downregulated, while several cytokines were unaffected (IL-6, IL-10, IL-1, and TNF-␣) (170). In addition, PPAR␥ agonists positively regulated CD86 expression whilst CD80 expression was downmodulated. These findings suggested that PPAR␥ activation modulated the polarization of DC-dependent immune response. The authors suggested that activation of PPAR␥ pathway in DCs favors the differentiation of naive T cells into type 2 cytokine-producing T lymphocytes (Th2 cells), since Th1 polarizing factor IL-12 profoundly decreased; in addition, the diminished production of IP-10 and RANTES may participate in the preferential recruitment of Th2 rather than Th1 lymphocytes. Notably, in these studies, cells were challenged with PPAR␥ activators during the maturation of DCs; however, some other reports investigated the ex vivo effect of PPAR␥ ligand during the course of DC development from monocytes. In these cases, ligand treatment had a profound inhibitory effect on the immunophenotype of DCs. Nencioni et al. (378) described that activation of PPAR␥ affected DC immunogenicity and reverted them to a less stimulatory mode. They confirmed the impaired IL-12 production, diminished CD80, and enhanced CD86 expression; however, several other cytokines (IL-6, IL-15, TNF) were also downregulated in the presence of PPAR␥ ligand (378). In addition, these cells expressed less CD40 and CD83, suggesting that PPAR␥-activated DCs conferred an impaired immunogenicity. Consistent with these findings, PPAR␥ ligand treatment severely blunted the T-cell activation capacity of these cells (378). This report also described that PPAR␥-instructed DCs expressed less CCR7, an important chemokine for DC migration. In line with this finding, murine Langerhans cells had an impaired migration capacity upon in vivo administration of PPAR␥ agonist (22). Interestingly, a reduced expression of CCR7 was also detected in bone marrow-derived, ovalbumin-pulsed DCs, and PPAR␥ activation also decreased the migratory capacity of these cells (186). In addition, in vivo administration of the PPAR␥ agonist pioglitazone reduced the tipDC (TNF/iNOS producing inflammatory DC) accumulation in lung upon H5N1 influenza A virus infection (16). It is possible that a PPAR␥-dependent impaired migration is responsible for the reduced recruitment of this DC subtype to the airway. The diminished DC immunity was also described in ex vivo murine DC models. Bone marrow-derived, PPAR␥ ligand-treated DCs also had an impaired T-cell activation capacity (262). Importantly, the negative effects of PPAR␥ ligand on DC priming were not observed in PPAR␥ knockout DCs, suggesting that these repressive effects were receptor dependent (262). In the macrophage section, we have already discussed in detail the potential mechanisms of the anti-inflammatory effects of PPAR␥ activators. It was suggested that PPAR␥ interfered with the NF-B pathway, which is important for the activation/maturation of DCs (397). Indeed, PPAR␥ agonist-treated, monocyte-derived DCs had diminished nuclear localization of c-Rel, a component of NF-B (23, 378). In addition, it seems that the MAP kinase pathway was also affected: PPAR␥-instructed DCs showed impaired phosphorylation of ERK kinase, and diminished phosphorylation of P38 was detected upon TLR4-dependent maturation (23). NF-B binding and impaired MAP kinase signaling pathway was also described in murine bone marrow-derived DCs, suggesting that it is a general repressive mechanism in DCs (262). Interestingly, activation of PPAR␥ leads Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 763 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Remarkably, a global gene expression profile analysis revealed that PPAR␥ was one of the highly upregulated transcription factors during IL-4/GM-CSF-driven monocytederived DC differentiation (279). The elevated expression of PPAR␥ was confirmed with more detailed transcript and protein analyses. Gosset et al. (170) described that PPAR␥ RNA and protein are highly upregulated upon human monocyte-derived DC differentiation, and later, others also observed robust induction of PPAR␥ upon DC development from monocytes (378, 502). In addition, our immunohistochemical analysis revealed that in human lymphoid tissue (tonsil) some of the S100 positive cells were also PPAR␥ positive, suggesting that in vivo, at least a subset of DCs also express PPAR␥ (502). PPAR␥ expression in DCs is not human specific, since CD11c splenic DCs also express this receptor (137) and PPAR␥ protein was also detected in murine bone marrow-derived DCs (186). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES to the upregulation of the coinhibitory molecule B7H1, and this inhibitory signal contributed for impaired activation of CD8⫹ T cells (263), suggesting that this mechanism is also part of the anti-inflammatory effects of PPAR␥. In summary, several lines of evidence suggested that activation of PPAR␥ has an adverse effect on DC immunity, maturation, and migration. The physiological role of this scavenger receptor on DCs is still controversial. It was suggested that CD36 had an important role for apoptotic cell uptake and cross presentation of antigens to cytotoxic T cells in human DCs (15). However, the CD36-deficient animal model revealed that CD36 is not essential for cross presentation of cellular antigens in vivo (59, 463). The other well-established PPAR␥ target is aP2 (alternative name FABP4). This adipose-specific fatty acid binding protein is a very abundant protein in fat cells (192). Remarkably, in monocyte-derived DCs, this transcript showed the highest upregulation upon PPAR␥ ligand treatment (502); in addition, the protein level was also strongly induced in PPAR␥-activated DCs (505). The potential role of this lipid binding protein in DCs is poorly characterized; however, bone marrow-derived DCs obtained from FABP4/aP2-deficient animals had impaired cytokine production (IL-12, TNF) and diminished T-cell activation capacity, suggesting that at least a low level of this protein positively regulated DC immunogenicity (443). Interestingly, one member of the ABC transporter family was directly regulated by PPAR␥ in monocyte-derived DCs. Our data revealed that PPAR␥ induced the expression of ABCG2 in differentiated human DCs; moreover, we identified a specific enhancer region containing three PPAR response elements in the upstream region of the ABCG2 gene (506) The ABCG2 protein is highly expressed in the plasma membrane of several drug-resistant cell lines, where it has been shown to extrude anti-tumor drugs (454); consistent with these findings, our results indicated that PPAR␥-instructed DCs had an enhanced xenobiotic extrusion capacity (526). Interestingly, besides the upregulation of individual genes, our global gene expression profile analyses revealed that a gene cluster and a few signaling pathways were also modulated in PPAR␥-instructed DCs. We 764 Our global gene expression analysis also indicated that PPAR␥ activation might modulate the lipid metabolism of DCs. A time course experiment of PPAR␥ ligand treatment revealed that genes involved in lipid metabolism comprised the primary class of transcripts changed in early stages of DC differentiation, while genes linked to immune responses were altered at later phases of DC development. These results suggested that PPAR␥ primarily modulated the lipid metabolism/transport in DCs and immune response-related genes are indirectly regulated (505). It is still unexplored how the two pathways are connected in DCs, but in macrophages it was suggested that lipid metabolism and immunity are interconnected (533). In summary, activation of the PPAR␥ pathway in DCs has detrimental effects; it is important to emphasize that most of these effects are receptor dependent, since these could be reverted by a PPAR␥ antagonist (GW9662) (21, 502). More importantly, conditional knockout data also revealed the receptor dependency (262). In addition, we found that several genes showed impaired induction/repression in PPAR␥-activated DCs obtained from patients harboring mutated PPAR␥ receptors (11, 505). In the future it would Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 However, in addition to these negative effects on DC development, we and others identified several pathways and target genes, which were positively regulated by PPAR␥ agonists. PPAR␥-activated monocyte-derived DCs had an enhanced FITC-dextran uptake capacity (23, 502). PPAR␥ ligand treatment resulted in increased mannose receptor expression in mouse DCs, which consequently led to enhanced mannose receptor-mediated endocytosis of soluble ovalbumin antigen (263). CD36 was one of the first identified PPAR targets in DCs (170, 378), and this receptor is implicated in antigen uptake. found that the lipid antigen presentation capacity of DC appears to be impacted by PPAR␥ activation via the coordinate regulation of CD1 proteins. CD1 proteins are MHC class I-like molecules that present lipid antigens to T cells; thus CD1s play an important role in acquired immunity. These proteins are divided into two groups: group 1 comprises CD1a, CD1b, CD1c, and CD1e and presents antigens derived from pathogenic microbes; group 2 contains only CD1d that is considered to present self-glycolipids, and this protein is necessary for generation and expansion of iNKT (invariant natural killer T) cells (36, 254). We detected a reduced expression of CD1a, -b, -c, and -e and an enhanced expression of CD1d in human PPAR␥ activated monocyte-derived DCs (502). The functional consequence of the elevated expression of CD1d was the selective expansion of iNKT cells (502). Recently, further mechanistic insights have been gained into this process by demonstrating that a lysosomal aspartyl protease, cathepsin D, is also regulated by PPAR␥ and also by RAR, and it contributes to the lipid antigen presentation process by cleaving ProSaposin and thereby facilitating lipid antigen processing (375) (FIGURE 5). We also found a connection between PPAR␥ and RAR pathways on CD1d regulation: PPAR␥-activated DCs had an enhanced ATRA production capacity, and some of the PPAR␥-dependent gene induction (CD1d and TGM2) was turned out to be indirectly regulated via the activation of RAR␣ nuclear receptor (506). We will discuss the potential connection between PPAR␥ and retinoid pathways in DCs in section XA. NAGY ET AL. be important to characterize the effects of PPAR␥ activators on DC development and function in vivo. G. Natural/Endogenous Ligands for Modulation of the PPAR␥ Pathway in DCs oxLDL contains several lipid species, which were described as PPAR␥ ligands (110, 371). DCs might also be engaged with oxLDL, and several reports documented the effects of oxLDL on DC development. We found that oxLDL indeed induced the expression of PPAR␥ targets (FABP4/aP2, CD1d); however, this effect was much less profound as a synthetic PPAR␥ activator (502). Some of the regulated genes were also induced by retinoids; thus it is possible that upregulation of CD1d was mediated by the retinoid content of the oxLDL (504). On the other hand, oxLDL promoted the maturation of DCs (101), and probably this is a PPAR␥independent signaling pathway since the pro-inflammatory lysophosphatidylcholine (LPC) could mediate this effect through the activation of a G protein-coupled receptor (100). Taken together, these results demonstrate that complex lipids like oxLDL have detrimental effects on DC activation and probably multiple pathways are involved. There are several other lipid compounds that were considered as PPAR␥ agonists in DCs. For instance, pollen grains contain pollen-associated lipid mediators; among these, E1 VIII. THE BIOLOGY OF VDR IN MACROPHAGES AND DENDRITIC CELLS A. Vitamin D and the Immune System: An Overview The immunomodulatory role of vitamin D first was demonstrated on T cells and B cells (289, 350, 440). The expression of VDR was documented in many human and murine immune cells, most importantly in macrophages, monocytes, DCs, T cells, B cells, and iNKT cells. Natural and synthetic VDR agonists can modulate a broad range of immune responses in these cells, and immunosuppressive effects of 1,25(OH)2D3 and its analogs also have been documented in in vivo animal models of immunemediated diseases such as autoimmune diabetes, experimental autoimmune encephalomyelitis, and allograft rejection. The regulatory role of 1,25(OH)2D3 on T cells and B cells is complex. 1,25(OH)2D3 inhibits T-cell proliferation and downmodulates the expression of IL-2, IFN-␥, and CD8⫹ T-cell mediated cytotoxicity, while IL-4 production is enhanced (44, 182, 288, 289, 332, 350, 428, 440, 441, 532). 1,25(OH)2D3 blocks the induction of Th1 cell and Th17 responses, while promoting Th2 cell and Treg responses Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 765 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 In the previous section we have demonstrated that activation of PPAR␥ exerted detrimental effects on differentiation and immunogenicity of DCs. Most of these studies used high-affinity, synthetic PPAR␥ activators; however, it is unclear whether the natural/endogenous PPAR␥ ligands can regulate these pathways in DCs or not. It is generally accepted that high concentration of polyunsaturated fatty acids, oxidized fatty acids, oxidized phospholipids, and several prostanoids can serve as natural ligands for PPAR␥. Interestingly, some of these lipid mediators also regulate the immune response; more importantly, migratory DCs might be exposed or even produce these lipid mediators. The first lipid mediator was prostaglandin D2 (PGD2) as potential activator of PPAR␥ in DCs. Angeli et al. (20) described that PGD2 inhibited the migration of Langerhans cells. Synthetic PPAR␥ agonists had similar inhibitory effects (21), suggesting that it might be a receptor-dependent effect. PGD2 binds to cell surface receptors, and it is unlikely to be a PPAR␥specific ligand. However, 15-dexoxy PGJ2 (15d-PGJ2), the dehydration end product of PGD2, is a high-affinity ligand of PPAR␥ receptor (141, 260). Interestingly, administration of 15d-PGJ2 had similar effects as troglitazone or rosiglitazone (well-established PPAR␥ activators) on DC differentiation and activation (378). However, it is worth mentioning that this lipid compound had some PPAR␥-independent effects (489); moreover, the physiological role of this molecule is still debated due to its low concentration in vivo (417). phytoprostane (PPE1) was suggested to be an activator of PPAR␥ (160). It is worth mentioning that this compound had a PPAR␥-dependent and -independent effect on DCs (160). Polyunsaturated fatty acids are natural ligands of PPAR␥. Consistent with this notion, doxosahexaenoic acid, a polyunsaturated fatty acid, had a similar effect as synthetic PPAR␥ activators on DCs (586). The authors assumed that these effects were mediated by activation of PPAR␥. However, this compound also binds RXR, suggesting that it can activate both partners of the PPAR:RXR heterodimer (586). Interestingly, our data indicated that the serum itself could modulate the activation stage of PPAR␥ in developing DCs. When monocyte-derived DCs were differentiated in human serum instead of fetal bovine serum, an elevated expression of several PPAR␥ targets (FABP4/ aP2, ABCG2) was detected, and this could be reverted with PPAR␥ antagonist, suggesting this to be a receptor-mediated process (502, 506). A more systematic gene expression profile analysis revealed that in human serum-cultivated DCs, a similar set of transcripts was upregulated as in synthetic PPAR␥ ligand-treated cells, indicating that a high affinity or high concentration of ligand might be present in or generated from human serum (505). The nature of such putative ligand is poorly defined; however, one study suggested that human serum-derived cardiolipin and lysophosphatidic acid might be responsible for the enhanced activation of PPAR␥ (291). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES (350). In addition to its inhibitory effects on T cells, 1,25(OH)2D3 decreases B-cell proliferation plasma cell differentiation and IgG secretion (81, 289, 350) acting directly on B cells, or via antigen presenting cells and/or T cell help (81, 350, 360, 471, 534). A recent study documented that VDR expression is required for the normal development and function of iNKT cells (583). In immune cells, 1,25(OH)2D3 regulates the gene expression by various molecular mechanisms. CYP24A1, CAMP, PPAR␦, and ALOX5 are upregulated directly by VDR:RXR (79, 130, 167, 480). Some immune functionrelated genes, e.g., IER3 and RelB, are downregulated directly via negative response element (126, 221). Ligand-bound VDR can also act by antagonizing the “inflammatory” transcription factors like NFATp/AP-1 and NF-B, which results in decreased expression of IL-2 and IL-12, respectively (106, 511). 1,25(OH)2D3 can also regulate gene expression by indirect mechanisms, by alteration of the level of enzymes, transcription factors, and coregulators (532). B. Effect of 1,25(OH)2D3 on Monocytes/ Macrophages The immunosuppressive effects of vitamin D on monocytes and macrophages are intensively investigated and well documented. 1,25(OH)2D3 inhibits the expression of all three subtypes of MHC class II antigens (HLA-DR, -DP, and -DQ) (572). VDR agonists exert strong immunosuppressive effects on IFN-␥-stimulated (but not on LPS-acivated) murine macrophages (194). Moreover, 1,25(OH)2D3 treatment leads to the inhibition of the listericidal activity, the inhibition of phagocyte oxidasemediated oxidative burst, and the suppression of IFN-␥induced genes, including CCL5, CXCL10, CXCL9, Fcgr1, Fcgr3, and TLR2 (194). However, many studies described the effects of 1,25(OH)2D3 distinct from its immunosuppressive capacity. Most importantly, 1,25(OH)2D3 or its analogs can initiate the differentiation of myeloid progenitors into macrophages (90, 266, 391). 1,25(OH)2D3 can also enhance the phagocytosis by monocytes (572). Administration of 1,25(OH)2D3 to mitogen-stimulated mononuclear cells caused an increase in prostaglandin E production (267). When added to peripheral blood monocytes, 1,25(OH)2D3 augmented IL-1 pro- 766 Remarkably, 1,25(OH)2D3-treated macrophages exhibit enhanced antimicrobial activity (103, 304, 444), because 1,25(OH)2D3 regulates genes encoding antimicrobial proteins, such as the cathelicid and defensin B. The antibacterial effects of macrophages will be discussed in details in section VIIIF. C. Effect of 1,25(OH)2D3 on DCs A number of studies provided evidence that 1,25(OH)2D3 inhibits differentiation, maturation, and immunostimulatory capacity of human and mouse DCs (10, 43, 150, 176, 177, 405, 412). The effect of 1,25(OH)2D3 on inhibiting the maturation of DCs was dependent on VDR (176). Molecular characteristics of 1,25(OH)2D3-treated DCs include low surface expression of MHC-II and costimulatory molecules (CD40, CD80, CD86); upregulation of inhibitory molecules (ILT3) decreased production of IL-12 and enhanced secretion of CCL22 and IL-10 (43, 150, 176, 177, 405– 408, 412). The inhibition of immunogenic pathways and the induction of “tolerogenic” molecules all together lead to a tolerogenic DC phenotype (352, 407). The tolerogenic properties of DCs induced by 1,25(OH)2D3 treatment are usually associated with the induction of Treg cells (FIGURE 5). However, tolerogenic pathways initiated by DCs can be also manifested in effector T-cell death and T-cell anergy. According to our study, 1,25(OH)2D3 can regulate transcription of several immune function-related genes, including genes the altered expression of which contributes to tolerogenic DC phenotype, independently of the differentiation process (507). The capacity of 1,25(OH)2D3-treated DCs to induce CD4⫹ CD25⫹ regulatory T cells that, besides its direct effects on T cells, can limit ongoing inflammatory responses make this ligand or its analogs (alone or in combination with other anti-inflammatory compounds) potential therapeutic targets (see below). D. Endogenous Production of 1,25(OH)2D3 in Macrophages and DCs 1,25(OH)2D3 is ⬃1,000 times less abundant in human serum than its precursor, 25(OH)D3 (206 –208). This concentration is insufficient to turn on 1,25(OH)2D3induced transcriptional changes in monocyte-derived DCs (507) and most likely in macrophages. Remarkably, a number of studies documented that both macrophages and DCs could produce 1,25(OH)2D3 from its precursors, suggesting that 1,25(OH)2D3 could act by an autocrine or paracrine fashion in these cells (8, 147, 171, Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 The in vitro effects of 1,25(OH)2D3 and its analogs on antigen presenting cells were documented by a number of studies on different macrophage and DC types. These studies demonstrated that cell subtypes could exhibit significant differences (e.g., conventional DCs vs. plasmacytoid DCs). It should be also noted that 1,25(OH)2D3 can play a different role in humans (daytime creatures that can synthesize vitamin D3 in the skin) and mice (nocturnal animals). duction (44). In addition, 1,25(OH)2D3 alters oxidative metabolism of monocyte/macrophage as demonstrated by human blood monocytes, which developed enhanced competence of secretion of H2O2 in the presence of 1,25 (OH)2D3 (91). NAGY ET AL. E. The Potential Role of Endogenously Produced 1,25(OH)2D3 in Triggering Negative-Feedback Mechanisms The fact that 1,25(OH)2D3 has immunosuppressive capacity suggests a potential negative-feedback mechanism in antigen-presenting cells (133, 182, 194, 198). According to this scenario, besides initiation of immunogenic responses, inflammatory stimuli can also induce the generation of a negative signal, 1,25(OH)2D3, that limits the extent of the immune responses and helps to avoid overstimulation (4, 95, 133, 194). As we could see in section VIII, B and C, endogenously produced 1,25(OH)2D3 can inhibit inflammatory pathways by various mechanisms. A recent study suggested another potential mechanism, demonstrating that 1,25(OH)2D3 can induce hyporesponsiveness to pathogens by downregulating the expression of TLR2 and TLR4 on monocytes (4, 451). The hypothesis of such a negative-feedback loop is supported by studies on VDR knockout animals. For example, VDR knockout mice are more resistant to intracellular protozoan Leishmania major infection than their wild-type littermates (133). Moreover, VDR knockout mice have larger subcutaneous lymph nodes than their wild-type littermates and contain increased number of mature DCs (176), most likely due to the lack of negative feedback of DC maturation. F. Antimicrobial Role of 1,25(OH)2D3 in Macrophage Detection of pathogens and initiation of immune responses are dominantly triggered by TLRs and other pattern recognition receptors (13, 226, 331, 415, 576). TLR2 activation by bacterial lipoproteins leads to killing of intracellular Mycobacterium tuberculosis in both mouse and human macrophages, albeit via distinct mechanisms (304, 517). In mouse macrophages, activation of TLR2/1 triggers the production of iNOS and consequently the release of nitric oxide (517). In human macrophages, the mechanism is nitric oxide-independent. The activation of TLR2/1 induces the expression of both VDR and CYP27B1, leading to an increased expression of VDR target genes, including antimicrobial peptides, cathlicidin, and defensin B2/4 (5) (167, 304, 548) (FIGURE 4). These peptides efficiently kill intracellular Mycobacterium tubercolosis. [TLR2/1-mediated expression of defb4 requires convergence of the IL-1 and VDR pathways (303).] Cathelicidin is not only necessary but also seems to be sufficient for vitamin D-mediated human antimicrobial activity (305). However, it is possible that this antimicrobial peptide is not the only mediator of antimicrobial activity (304). The identified 1,25(OH)2D3dependent antimicrobial mechanism could explain a series of previous observations (302, 304, 305). First, both heliotherapy (sun exposure or ultraviolet light) and cod liver oil are efficient in the treatment of tuberculosis (reviewed in Ref. 422). A well-known acknowledgement of the success of such trials was Niels Ryberg Finsen’s Nobel Prize in Physiology or Medicine in 1903 for his contribution to the treatment of diseases, especially lupus vulgaris (cutaneous tuberculosis), with concentrated light radiation. Second, vitamin D deficiency is associated with tuberculosis (563), and VDR variations confer increased susceptibility to Mycobacterium tuberculosis infection in humans (38, 563). Third, 1,25(OH)2D3 induces an antimicrobial activity against Mycobacterium tubercolosis of cultured monocytes/macrophages (103, 442, 444, 476). Last, African Americans are known to have increased susceptibility to Mycobacterium tuberculosis infection (204, 304), most likely because of the lower level of vitamin D3 and cathelicidin D. Supplementation of the African American serum with 25(OH)D3 to a physiological range restored TLR induction of cathelicidin mRNA (204, 304). Remarkably, correlation between insufficient vitamin D status and ulcerative colitis and Crohn’s disease was also documented (204). More recent findings illustrate how vitamin D deficiency may be a cause for these conditions. Nod2 (Card15) gene, encoding an intracellular pattern recognition receptor, has been identified as a direct target gene of VDR (547). Because Crohn’s disease pathogenesis is associated with attenuated NOD2 (218, 389), this study provides a molecular mechanism to explain the Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 767 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 198, 269, 426 – 428). The key feature of endogenous 1,25(OH)2D3 production is the upregulation of enzymes involved in the synthesis of 1,25 (OH)2D3. As we could see previously, the inactive 25(OH)D3 is converted to 1,25(OH)2D3 by CYP27B enzyme. (Most likely this second hydroxylation is the limiting step in antigen presenting cells.) Interestingly, while the expression of CYP27B1 in the kidney are inhibited by many signals [e.g., calcium, parathyroid hormone, phosphate, and 1,25(OH)2D3 itself (94, 143, 149, 199, 364, 416, 429, 526)], antigen presenting cells seem to lack responsiveness to these inhibitory signals (7, 183, 199, 426). In contrast, CYP27B1 is upregulated in macrophages and/or DCs by various maturation/activation stimuli, including IFN-␥, IL-2, LPS, TLR2/1-activator, CL075, CD40 ligation, TNF-␣, and polyI:C (6, 7, 147, 198, 304, 419, 426, 427, 507). In some cases, responses of macrophages and DCs are different. For example, synthetic 19-kDa Mycobacterium tuberculosis-derived lipopeptide upregulates CYP27B1 in monocytes and macrophages, but not in DCs (304). Some agents, e.g., LPS, TLR2/1L, and CL075, are able to induce the expression of both VDR and CYP27B1, leading to elevated receptor and ligand levels simultaneously. The inactivation of 1,25(OH)2D3 is carried out predominantly by the CYP24A1 enzyme, which is a direct VDR target gene. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES connection between vitamin D deficiency and the genetics of Crohn’s disease. Another study demonstrated that impaired vitamin D leads to dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria (277). DNA array analysis of colon tissue also identified many genes, including angiogenin-4, an antimicrobial protein being consistently downregulated in vitamin Ddeficient mice providing a pivotal mechanism linking vitamin D status with inflammatory bowel disease in humans (277). G. Therapeutic Considerations of 1,25(OH)2D3 Animal studies also demonstrated that vitamin D and its analogs can prevent the development of various autoimmune diseases, including systemic lupus erythematosus, experimental allergic encephalomyelitis, collagen-induced arthritis, Lyme arthritis, inflammatory bowel disease, and autoimmune diabetes in NOD mice (reviewed in Ref. 326). To some extent, they are also effective in the treatment of these diseases. In addition, VDR agonists prolong allograft survival in a variety of experimental models supporting a further potential pharmacological application for this hormone or its analogs (9, 326). Vitamin D deficiency is also among risk factors of tuberculosis infection (381). Apparently, vaccination and antibiotics are the most effective way of prevention and treatment of tubercolosis, but vitamin D can also increase resistance to infection, especially in nonvaccinated people (385, 422). Clinical trials of adjunctive vitamin D 768 IX. COMPLEXITY OF GENE REGULATION BY NUCLEAR RECEPTORS: FROM PATHWAYS TO NETWORKS It appears that there are extensive interactions between nuclear receptor-regulated events and also other signaling and transcription networks. A nice documentation of such interaction between TLR and nuclear receptor signaling was provided by Glass and colleagues (388), who were able to show that while the glucocorticoid receptor-mediated transcriptional repression takes place by the disruption of the p65/IRF complex, PPAR␥ and LXR-mediated repression is independent of this pathway. Here we attempt to classify the various modes of interactions and illustrate these with examples we already detailed above. Analyses of cell surface markers as well as functional tests and gene expression profiling demonstrated that agonists for RXR, RAR, LXR, PPAR, and VDR regulate overlapping sets of genes and functions in macrophages and DCs (508). This phenomenon is due to the fact that activation of nuclear receptors is resulted in parallel signaling and crosstalk between these receptors (FIGURE 7). These observations suggest that instead of isolated pathways, one must consider networks involving nuclear receptors, cofactors, and enzymes that participate in the production of active ligands. Others and also us could present evidence for this parallel signaling and cross-communication between nuclear receptors, many of them take place in macrophages and DCs. Some examples are given here and are illustrated on FIGURE We could identify four distinct modes of interactions. 1) Many natural ligands can activate more then one nuclear receptors, e.g., ATRA is a ligand for both RAR and PPAR␦, while DHA can regulate both RXR and PPAR (116). RXR agonists induce several pathways in parallel, because they can regulate RXR homodimers and many permissive heterodimers, e.g., LXR:RXR and PPAR:RXR (508). The biological relevance of this redundancy is not clear. 2) One nuclear receptor can serve as a sensor and be activated by multiple ligands. For example, PPAR␥ is regulated by various modified fatty acids and prostanoids. 3) Some nuclear receptors are primary targets of other nuclear receptors, e.g., LXR␣ and PPAR␦ are regulated by PPAR␥ (77) and VDR (130), respectively. 4) One receptor can modify the activity of other nuclear receptors and transcription factors. This is carried out by regulating the expression of co-factors, enzymes, and scavenger receptors and by antagonizing other transcription factors. For example, RAR can induce the expression of RIP140, which could influence RAR and PPAR signaling (146, 558). A particularly intriguing example of the crosstalk is the regulation of endogenous ligand 7. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 It has been estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency [25(OH)D3 serum level below 50 nM] (204). Many aspects of vitamin D deficiency are discussed in details in a recent review (204). Rickets and osteomalacia are well known but are rather extreme examples of the effects of vitamin D deficiency. 1,25(OH)2D3 has a broad range of biological activities, and it is not surprising that vitamin D insufficiency can raise the risk for various diseases and susceptibility for infections. Living at higher latitudes (where UVB doses are lower) increases the risk of various types of cancer. Furthermore, correlations have been found between higher latitudes and risk of type 1 diabetes, multiple sclerosis, Crohn’s disease, hypertension, and cardiovascular disease (204). In parallel, vitamin D supplementation could reduce the risk for developing autoimmune diseases, e.g., multiple sclerosis, rheumatoid arthritis, and osteoarthritis, as well as of type I diabetes (204, 329, 337, 362). Although in many cases the correlation between D insufficiency and the risk for the disease is clearly demonstrated, the exact mechanisms for vitamin D effect and the target cell types are not defined. therapy in active tuberculosis are reviewed in Reference 422. NAGY ET AL. production. There are multiple examples for such activity in macrophages and DCs. For example, we have shown that PPAR␥ can transform DCs to RA-producing cells providing ligand for RARs (504), also the dual regulation of CYP27 by RAR and PPAR␥ leads to increased ligand production for LXR (498). Nuclear receptors, e.g., GR, VDR, LXRs, and PPARs, are described and considered as negative regulators of many inflammatory responses. A unique crosstalk between these nuclear receptors and other transcription factors (e.g., NF-B, AP-1, and IRFs) has been documented in the process of transrepression (162), suggesting that one must investigate signaling pathways together to understand the effects of nuclear receptors. Novel technologies (e.g., microarray, ChIP-chip, GRO-Seq, RNA-Seq, additional new-generation sequencing technologies, etc.) revealed and continue to reveal another level of complexity of transcriptional networks on the promoter/enhancer regions of genes. These technologies are likely to be transformative in terms of providing large genome scale datasets. For example, C/EBPs were reported to bind to the vicinity of PPAR␥ response elements in adipocytes (282, 380). Recently, we could show such an interaction exists between PPAR␥ and the transcriptional mediator of IL-4 signaling STAT6 (497). This interaction and the facilitating role of STAT6 for PPAR␥ signaling provides a plausible explanation for the enhanced receptor activity in IL-4-exposed alternatively activated macrophages and DCs. Further similar interactions are expected to be uncovered by genome-wide localization and profiling approaches. As more and more such interactions are revealed, the interpretation and analysis of data require the implementation of mathematical models. One can identify well-established regulatory logic circuit elements such as autoregulation of LXR expression in human cells (562), positive feedback loop in the induction of the scavenger receptor CD36 by PPAR␥, which leads to increased oxLDL uptake and further activation of PPAR␥ or regulatory chains or cascades when RAR facilitates PPAR␥ signaling and that in turn activates LXR (77, 520) (FIGURE 7). Genome-wide analyses might contribute to the identification of further interactions and reveal the regulatory logic of lipid signaling via nuclear receptors in these cell types. These analyses eventually will lead to true system level understanding of these processes especially if integrated to other transcriptional networks such as NF-B, etc. X. LIGAND PRODUCTION BY DENDRITIC CELLS IS INVOLVED IN DETERMINATION OF T-CELL HOMING AND DEVELOPMENT Although it is a key issue to determine how endogenous ligands are produced for nuclear receptors in macrophages and DCs, it is also conceivable that these cells themselves may serve as sources of ligands for other cells of the immune system, therefore contributing to paracrine nuclear receptor ligand signaling. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 769 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 FIGURE 7. Distinct logic circuits can be identified among the various interactions of nuclear receptor pathways in macrophages. A: “single input”: one ligand (L) can activate more than one RXR heterodimer (NR1, NR2, and NR3). For example, docosahexaenoic acid (DHA) can regulate both RXR and PPAR. B: “multiple input”: one nuclear receptor (NR) is activated by several agonists. For example, the relatively large ligand-binding pocket of PPAR␥ can bind a broad range of natural and synthetic ligands. C: nuclear receptors can regulate the transcription of their own (NR1) and other nuclear receptors (NR2-NR6). “Autoregulation”: LXR␣ regulates its own transcription in human cells. VDR regulates the expression of PPAR␦. “Regulatory chain”: RAR enhances PPAR␥ response and PPAR␥ turns on LXR␣ gene expression. D: nuclear receptors can modify the activity of other nuclear receptors and transcription factors. Many nuclear receptors, e.g., VDR, LXRs, and PPARs, are considered as negative regulators of other transcription factors (TF) such as NF-B and AP-1. PPAR␥ regulates the expression of CD36 scavenger receptor (SR). Upregulation of CD36 leads to increased oxidized LDL uptake and PPAR␥ activation. The level of endogenous ligands can be regulated by inducing enzymes involved in the ligand conversion. For example, PPAR␥ can transform DCs to retinoic acid producing cells providing ligand for RAR. One receptor could indirectly influence the activity of another nuclear receptor by regulating the expression of certain cofactors. For example, RAR can induce the expression of RIP140, which could influence RAR and PPAR signaling (NR1, NR2). NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES A. Retinoic Acid Production by DCs It is intriguing which factors modulate the ATRA production capacity of DCs. It is possible that some antigen presenting cells (CD103⫹ DCs) have an inherent capac- 770 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Emerging data suggested that various subsets of intestinal DCs can produce retinoic acid, more precisely ATRA, and this locally generated compound shapes the intestinal immune response via a paracrine modulation of lymphocyte development/activation. First, Iwata et al. (228) described that mesenteric lymph node (MLN) and Peyer patch (PP) DCs, isolated from mouse intestine, are able to produce ATRA in vitro (228). Consistent with this finding, these cells expressed several genes, which might be responsible for ATRA production, for example, MLN DCs expressed the transcript of alcohol dehydrogenase III and Raldh2 (aldh1a2) (228). ATRA is the active form of vitamin A, which is generated after two consecutive oxidation steps from retinol (vitamin A). First, retinol is oxidized to retinaldehyde (retinal) and then this compound is converted to ATRA. The first step is catalyzed by alcohol dehydrogenases and/or short-chain dehydrogenases/reductases (some of them are called retinol dehydrogenases), and the second irreversible step is catalyzed by retinaldehyde dehydrogenase (Raldhs) (129). It is still controversial which enzyme activities catalyze in vivo these reactions; however, genetic data indicated that, at least during early embryonic development, Raldh2 enzyme has a pivotal role (379). It seems that Raldh2 also had an important role for the production of DC-derived ATRA. The CD103⫹ subset of PP and MLN murine DCs highly expressed Raldh2, and these cells profoundly stimulated regulatory T-cell (Treg) development. Moreover, RAR antagonist (LE540, LE135) efficiently blocked Treg formation, suggesting that ATRA production was important for this step (97). Interestingly, a follow-up study revealed that a similar CD103⫹ DC population was detected in human mesenteric lymph nodes, and these human cells might also produce ATRA since the DC-dependent induction of gut homing receptors (CCR9 and ␣47) on T cells was blocked with a RAR antagonist (229). Gut-specific DC population is rather heterogeneous, a macrophage-like DC subtype (CD11c/CD11b double-positive cells) was isolated from the lamina propria, which expressed Raldh2 and produced ATRA (527). Of note, intestinal macrophages could also synthesize ATRA (121, 242); in addition, gutassociated stromal cells might also contribute to ATRA production (187, 343). These findings demonstrated that at least a few subsets of intestinal DCs can generate ATRA, and this is a gut-specific propensity of the DCs. However, a recent study described that a subset of migratory DCs derived from skin and lung was able to produce ATRA and induce Treg development, suggesting that ATRA-producing DCs are not restricted to the intestine (181). ity to produce ATRA, more likely that the local environment instructs these cells to generate ATRA. Much effort has been applied over the past few years to identify the signaling pathways that modulate the ATRA production capacity of DCs. Our global gene expression profile analysis suggested that human PPAR␥-instructed DCs generate ATRA. We found that several genes were upregulated, which participate in retinol/retinal oxidation (504). More importantly, our liquid chromatographymass spectrometry analysis indicated that these PPAR␥ ligand-treated DCs produced ATRA ex vivo. There are conflicting reports on the effects of PPAR␥ activators in mouse DCs. Iwata and co-workers’ (578) analysis indicated that PPAR␥ ligand failed to induce RALDH2 expression in Flt3L-induced murine bone marrow-derived DCs; however, PPAR␥ activation enhanced Treg generation through increased ATRA synthesis in murine splenic DCs (215). It should be mentioned that our gene expression analysis revealed that besides the elevated expression of RALDH2, one of the retinol dehydrogenases (RDH10) was also upregulated in PPAR␥ ligand-treated DC. It is controversial whether the first or the second oxidation step is the rate limiting for the in vivo ATRA synthesis. Retinol conversion to retinal is catalyzed by many enzymes (at least in vitro), suggesting that this step has no role in the spatial or temporal regulation of ATRA synthesis (129). However, this notion has been challenged recently: RDH10 plays a critical role in embryonic ATRA synthesis, and loss of RDH10 function disrupts ATRA production during embryonic development (453). Consistent with this notion, it was also documented that a special gut-specific human antigen presenting cell (having shared DC and macrophage markers) also had an elevated expression of RDH10, suggesting that this enzyme activity might contribute to the ATRA generation at least in human cells (242). Our data also indicated that human monocyte-derived DCs had a relatively high expression of Raldh2. Importantly, this in vitro DC differentiation is driven by IL-4 and GM-CSF cytokines; hence, it is possible that these cytokines might participate in the regulation of Raldh2 expression. Indeed, IL-4 had a positive effect on the expression of Raldh2 in mesenteric lymph node DCs, and IL-4 receptor-deficient cells had a reduced expression of Raldh2 (134). Additionally, GMCSF also stimulated Raldh2 expression both in bone marrow-derived and splenic DCs, and this induction was enhanced in the presence of IL-4. Moreover, GM-CSF receptor-deficient animals showed an impaired intestinal ATRA production (578). Notably, in this report, SPF pathogen-free condition was applied since it turned out that TLR activators also enhanced RA production (578). In line with this finding, TLR2 ligand (zymosan) profoundly promoted the Raldh2 expression in splenic DCs (320). In addition, this TLR2-dependent Raldh2 induction was blocked with ERK kinase or syk kinase inhibitors, suggesting that these intracellular signaling path- NAGY ET AL. B. Modulation of Intestinal Immunity by DCs Via Production of Retinoic Acid One of the major breakthroughs in DC biology was the deciphering of molecular mechanisms of gut-specific lymphocyte imprinting and oral tolerance (FIGURE 8). Several lines of evidence suggested that DC-derived ATRA signaling has a central role in these processes. It was preciously observed that expression of the gut-homing receptors (␣47 integrin and CCR9) was essential for the preferential homing of T cells to the intestine (185, 494). Iwata and co-workers discovered that ATRA enhanced the expression of these gut homing receptors (␣47 and CCR9) in T lymphocytes. Moreover, they found that T cells that were primed in the presence of ATRA showed a preferential gut homing specificity (228). Notably, DC-derived ATRA was FIGURE 8. The role of all-trans-retinoic acid and 1␣,25-dihydroxyvitamin D3 in T-cell homing and lymphocyte specification. A: schematic representation of the interaction between an activated DC and a lymphocyte. Nuclear receptor ligands are involved in the polarization and homing of lymphocytes. B: contribution of all-trans-retinoic acid (ATRA) and 1␣,25-dihydroxyvitamin D3 [1,25(OH)2D3] to the development of gut or epidermis homing phenotype of T cells, respectively. C: role and contribution of ATRA to the development of regulatory T cells and IgA-producing B cells. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 771 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 ways might participate in the positive regulation of this key enzyme of RA synthesis. Of note, intestinal DCs and macrophages derived from -catenin null mice expressed much lower amounts of Raldh1 and -2 transcripts and proteins compared with wild-type cells. These data suggested that the -catenin pathway directly or indirectly modulates the ATRA-producing capacity of the intestinal antigen-presenting cells (321). Interestingly, ATRA itself could directly induce Raldh2 in DCs, suggesting that ATRA enhances its own synthesis (344). Finally, a negative regulator of the ATRA synthesis was also identified: prostaglandin E2 enhanced the expression of the inducible cAMP early repressor, which appears to directly inhibit RALDH expression in DCs (488). Taken together, these results demonstrated that at least in vitro several signaling pathways contribute to the regulation of DCspecific ATRA synthesis. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES also important for gut tropism in B cells (349). Numerous reports confirmed the ATRA-dependent induction of these receptors on T cells; however, it is still poorly characterized the ATRA-mediated regulation of ␣47 and CCR9. CCR9 expression seemed to be more dependent on ATRA than ␣47. Moreover, a functional cooperation was recently described between NFATc2 and the RAR:RXR heterodimer complex on the promoter region of the mouse Ccr9 gene, suggesting that ATRA directly modulates the expression of CCR9 (390). It seems that the effect of ATRA on T-cell regulation is more complex. Although it enhances TGF--mediated Foxp3⫹ T cell development, ATRA represses IL-10 production of these cells. Consistently vitamin A-deficient mice have enhanced IL-10-producing iTreg cells (328). Unexpectedly, ATRA was required to provoke a pro-inflammatory T-cell response to infection and mucosal vaccination. It seems that T cell specific RAR␣ was the critical receptor of these effects: inhibition of the RAR signaling and deficiency in RAR␣ resulted in a cell-autonomous CD4⫹ T cell activation defect (184). In addition, ATRA can elicit a proinflammatory phenotype in intestinal DCs to dietary antigens in a murine model of celiac disease. It was observed that ATRA synergizes with IL-15 to promote the breakdown of gluten tolerance and potentiate production of IL-12 and IL-23 by mucosal DCs (122). These unexpected results indicated that 772 C. Connection Between 1,25(OH)2D3 Released by DCs and Epidermal Lymphocyte Homing Similarly to ATRA, 1,25(OH)2D3 was also implicated in ligand-induced lymphocyte trafficking (FIGURE 8). CCR10 is a chemokine receptor, expressed by 1% of CD8⫹ T cells and 5% of CD4⫹ T cells (474). Its ligand, CCL27, is a chemoattractant, selectively expressed by keratinocytes of the epidermis. This chemokine is thought to mediate and/or influence the epidermotropism of CCR10⫹ T cells from dermis, the retention of T cells in or near the epidermis, and the homing of cells from the blood into the vascular dermis (210, 351, 432, 474). The expression of CCR10 in human T cells and the migration of T cells toward CCL27 were significantly induced in the presence of 1,25(OH)2D3, especially when added together with IL-12 (474). Further experiments showed that naive but not memory or previously activated T cells required IL-12 for efficient 1,25(OH)2D3mediated induction of CCR10. In the promoter of CCR10, a DR3-type VDRE has been identified, suggesting a direct ligand-dependent regulation (474). 1,25(OH)2D3 alone or with IL-12 upregulate CCR10 in mouse T cells as well, albeit not as efficiently as in human T cells. The concentrations found in normal serum were ineffective to induce the CCR10 level of T cells. Importantly, monocyte-derived DCs themselves and T cell-DC cocultures could convert vitamin D3 to 1,25(OH)2D3, because both hydroxylation steps could be accomplished by DCs (see above). It should be noted that T cells could convert only 25(OH)D3 to 1,25(OH)2D3. These results do not exclude the possibility that other cell types, e.g., keratinocytes, could also process vitamin D to 1,25(OH)2D3 in the skin. In agreement with these results, 25(OH)D3 and vitamin D itself could induce CCR10 expression on T cells interacting with antigen presenting DCs. Sigmundsdottir et al. (474) could document the ability of skin-associated DCs to metabolize the sunlight-induced vitamin D using DCs obtained by cannulating an afferent lymph vessel draining site of chronic skin inflammation in sheep. The survey on the effect of 1,25(OH)2D3 on other molecules important for skin homing helps to address which aspect of T-cell migration is affected by 1,25(OH)2D3. Migration of effector and memory T cells relies on the expression of ligands for E- and P-selectin and CCR4 and CCR10 (348, 350). 1,25(OH)2D3 failed to induce the expression of CCR4 and other skin homing-associated chemokine receptors CCR6 and CCR8 (348, 350). Moreover, 1,25(OH)2D3 blocks the upregulation of ligands of E-selectin and the expression of fucosyl- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 In addition to T-cell tropism, DC-derived ATRA also facilitates the B-cell IgA secretion along with the commensural flora and TSLP. Moreover, vitamin A-deficient mice lacked IgA-secreting cells, suggesting the in vivo relevance of this regulation (349). After the identification of the gut homing tropism of retinoid signaling, it was found that ATRA also participated in the regulation of oral tolerance. Oral tolerance is the immunologic mechanism by which the gut immune system maintains unresponsiveness to antigens upon enteral uptake. Several lines of evidence suggested that inducible regulatory T cells (iTregs) have an important role in the maintenance of gut immune tolerance (105). Remarkably, intestinal DC-derived ATRA signaling elicited iTreg development via a synergy with TGF- (355). This finding was confirmed by others, and an ATRA-producing DC subtype (CD103⫹ cells) was identified that modulates these processes (42, 97, 492). The mechanism of ATRA-dependent iTreg regulation is still poorly characterized; however, one report suggested that RAR␣ activation directly induced histone acetylation in the promoter of FoxP3 (a master regulator of iTreg development) (105), hence activating this key gene (245). We have to note that it is still unclear whether ATRA directly stimulates iTreg differentiation or this is an indirect effect; one report suggested that ATRA indirectly regulates this process through the negative regulation of CD44 high T cells (201, 356) (FIGURE 8). in a stressed intestinal environment, ATRA can act as an adjuvant that promotes rather than represses inflammatory responses. Taken together, these results suggested that DCderived ATRA has a complex role on shaping lymphocyte activation and polarization in gut-associated lymphoid tissue. NAGY ET AL. transferase-VII, an enzyme essential for the synthesis of selectin ligands (316, 350, 474, 574). Remarkably, 1,25(OH)2D3 inhibited T-cell homing to the inflamed skin (574). These data collectively suggest that 1,25(OH)2D3 does not mediate T-cell recruitment from the blood. Instead, 1,25(OH)2D3 may act on T cells directly in the skin, after T cells infiltrated the dermis, inducing CCR10 to generate a T-cell attraction signal toward (and/or retention in) the epidermis. XI. CONCLUSIONS AND PERSPECTIVES From a molecular endocrinologist, “receptorologist” point of view, simply the large-scale identification of primary and secondary nuclear receptor targets proved to be very useful. At the same time, the relatively easy accessibility and availability of these cell types from both humans and mice makes these cells ideal for ex vivo culture and study. In particular, the possibility of analyzing multiple interacting pathways simultaneously in normal human or murine homogeneous cell populations is a unique opportunity. For example, issues such as the nature of RXR activation in the context of several heterodimers could be addressed. The identified target genes and pathways then could and should be verified and followed up in genetic models in vivo, which is a more tedious task, and these can contribute to a better understanding of receptor activity, interaction, and networking. Also, the molecular details of target gene activation and repression can be dissected at a genomic scale. From an immunologist point of view, the introduction of nuclear receptors as modulators of immune cell differentiation and function provides an approachable system to probe the plasticity of macrophages and DCs and also to uncover the regulatory logic of immune cell differentiation, not in small part thanks to the availability of synthetic ligands. For example, we find it remarkable that simply applying lipids on DCs one can generate a range of activities leading to various T-cell subpopulations and also changing their relative amounts (FIGURE 5). These experiments also showed that activation of nuclear receptor pathways have specific effects rather than general peiotropic ones on the differentiation and function of immune cells. A key outstanding issue is to determine to what degree these pathways are utilized in vivo and how endogenous ligand From a more clinical and practical point of view, the identification and characterization of nuclear receptor-mediated pathways in these key immune cells are likely to contribute to a better understanding of disease mechanisms and potentially opening the door for the development for therapeutic approaches in chronic inflammatory diseases and autoimmunity. However, there is much more to do: more emphasis should be put on the systems level analyses, animal models in which genetic elimination of a particular receptor is possible in a given cell type at will; more thorough lipidomics to determine which are the active metabolic pathways and also more human clinical studies are required to avoid or bypass species specific phenomena and to convince even skeptics about the viability of such approaches and ease the translation of key findings to the clinic. ACKNOWLEDGMENTS The authors are indebted to Dr. Eva Rajnavolgyi and members of the Nagy laboratory for comments on the manuscript and Csaba Antal for artwork. Present addresses: A. Szanto, Howard Hughes Medical Institute, Dept. of Molecular Biology, Massachusetts General Hospital, Dept. of Genetics, Harvard Medical School, 185 Cambridge St., Boston, MA 02114; L. Széles, Dept. of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1 Rue Michel-Servet, 1211 Geneva, Switzerland. Address for reprint requests and other correspondence: L. Nagy, Dept. of Biochemistry and Molecular Biology, Univ. of Debrecen, Medical and Health Science Center, Egyetem tér 1, Debrecen, Hungary H-4010 (e-mail: nagyl@med. unideb.hu). GRANTS L. Nagy is an International Scholar of the Howard Hughes Medical Institute and holds a Wellcome Trust Senior Research Fellowship in Biomedical Sciences. He is also supported by a grant from the Hungarian Science Research Fund (OTKA NK72730), TAMOP-4.2.2/08/1, and TAMOP-4.2.1/B-090/1/KONV-2010-0007 implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 773 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 The remarkable versatility and plasticity of macrophages and DCs makes them an ideal target for studying the activity of lipid-activated transcription factors, nuclear receptors. The last 15 years have brought a significant advance in this field. This was not in small part due to the availability of gene expression profiling and other genome-wide approaches. Now the contribution of retinoid, fatty acid, cholesterol, and prostanoid compounds via nuclear receptors on cell type specification and differentiation has been accepted by the immunology community. production is regulated. Also, it should be explored how these pathways interact with each other and with key inflammatory transcriptional responses such as NF-B, AP1, or STATs. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES REFERENCES 19. Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW. Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem 264: 8222– 8229, 1989. 1. A IUPAC IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of vitamin D recommendations 1981. Mol Cell Biochem 49: 177–181, 1982. 2. Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison BB, Gumucio DL, Marin HE, Peters JM, Young HA, Gonzalez FJ. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut 55: 1104 –1113, 2006. 3. Adams J, Kiss E, Arroyo AB, Bonrouhi M, Sun Q, Li Z, Gretz N, Schnitger A, Zouboulis CC, Wiesel M, Wagner J, Nelson PJ, Grone HJ. 13-Cis retinoic acid inhibits development and progression of chronic allograft nephropathy. Am J Pathol 167: 285–298, 2005. 4. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 4: 80 –90, 2008. 6. Adams JS, Modlin RL, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. J Clin Endocrinol Metab 69: 457– 460, 1989. 7. Adams JS, Ren SY, Arbelle JE, Horiuchi N, Gray RW, Clemens TL, Shany S. Regulated production and intracrine action of 1,25-dihydroxyvitamin D3 in the chick myelomonocytic cell line HD-11. Endocrinology 134: 2567–2573, 1994. 8. Adams JS, Singer FR, Gacad MA, Sharma OP, Hayes MJ, Vouros P, Holick MF. Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab 60: 960 –966, 1985. 9. Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 4: 404 – 412, 2008. 10. Adorini L, Penna G, Giarratana N, Roncari A, Amuchastegui S, Daniel KC, Uskokovic M. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol 89 –90: 437– 441, 2004. 11. Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, Rajanayagam O, Semple R, Luan J, Bath L, Zalin A, Labib M, Kumar S, Simpson H, Blom D, Marais D, Schwabe J, Barroso I, Trembath R, Wareham N, Nagy L, Gurnell M, O’Rahilly S, Chatterjee K. Non-DNA binding, dominant-negative, and human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metab 4: 303–311, 2006. 12. Agura ED, Howard M, Collins SJ. Identification and sequence analysis of the promoter for the leukocyte integrin beta-subunit (CD18): a retinoic acid-inducible gene. Blood 79: 602– 609, 1992. 13. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 4: 499 –511, 2004. 14. Akiyama TE, Sakai S, Lambert G, Nicol CJ, Matsusue K, Pimprale S, Lee YH, Ricote M, Glass CK, Brewer HB Jr, Gonzalez FJ. Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Mol Cell Biol 22: 2607–2619, 2002. 15. Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188: 1359 –1368, 1998. 16. Aldridge JR Jr, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA, Doherty PC, Webster RG, Thomas PG. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci USA 106: 5306 – 5311, 2009. 17. Alleva DG, Johnson EB, Lio FM, Boehme SA, Conlon PJ, Crowe PD. Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by IFN-gamma. J Leukoc Biol 71: 677– 685, 2002. 18. Anderson KL, Perkin H, Surh CD, Venturini S, Maki RA, Torbett BE. Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor-derived dendritic cells. J Immunol 164: 1855–1861, 2000. 774 21. Angeli V, Hammad H, Staels B, Capron M, Lambrecht BN, Trottein F. Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol 170: 5295–5301, 2003. 22. Angeli V, Llodra J, Rong JX, Satoh K, Ishii S, Shimizu T, Fisher EA, Randolph GJ. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 21: 561–574, 2004. 23. Appel S, Mirakaj V, Bringmann A, Weck MM, Grunebach F, Brossart P. PPAR-gamma agonists inhibit toll-like receptor mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood 2005. 24. Auffray C, Fogg DK, Narni-Mancinelli E, Senechal B, Trouillet C, Saederup N, Leemput J, Bigot K, Campisi L, Abitbol M, Molina T, Charo I, Hume DA, Cumano A, Lauvau G, Geissmann F. CX3CR1⫹ CD115⫹ CD135⫹ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J Exp Med 206: 595– 606, 2009. 25. Babaev VR, Yancey PG, Ryzhov SV, Kon V, Breyer MD, Magnuson MA, Fazio S, Linton MF. Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 25: 1647–1653, 2005. 26. Babiker A, Andersson O, Lindblom D, van der Linden J, Wiklund B, Lutjohann D, Diczfalusy U, Bjorkhem I. Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J Lipid Res 40: 1417–1425, 1999. 27. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O’Malley BW. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 85: 3294 –3298, 1988. 28. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 392: 245–252, 1998. 29. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54: 2351–2359, 2005. 30. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM. PPAR gamma is required for placental, cardiac, adipose tissue development. Mol Cell 4: 585–595, 1999. 31. Barlic J, Zhang Y, Foley JF, Murphy PM. Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway. Circulation 114: 807– 819, 2006. 32. Barton AE, Bunce CM, Stockley RA, Harrison P, Brown G. 1 alpha,25-Dihydroxyvitamin D3 promotes monocytopoiesis and suppresses granulocytopoiesis in cultures of normal human myeloid blast cells. J Leukoc Biol 56: 124 –132, 1994. 33. Beard RL, Colon DF, Song TK, Davies PJ, Kochhar DM, Chandraratna RA. Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid. J Med Chem 39: 3556 –3563, 1996. 34. Becker S, Daniel EG. Antagonistic and additive effects of IL-4 and interferon-gamma on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens, and superoxide production. Cell Immunol 129: 351–362, 1990. 35. Bedford PA, Knight SC. The effect of retinoids on dendritic cell function. Clin Exp Immunol 75: 481– 486, 1989. 36. Behar SM, Porcelli SA. CD1-restricted T cells in host defense to infectious diseases. Curr Top Microbiol Immunol 314: 215–250, 2007. 37. Behre G, Whitmarsh AJ, Coghlan MP, Hoang T, Carpenter CL, Zhang DE, Davis RJ, Tenen DG. c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. J Biol Chem 274: 4939 – 4946, 1999. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 5. Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the human immune response. Ann NY Acad Sci 1117: 94 –105, 2007. 20. Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron M, Trottein F. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med 193: 1135–1147, 2001. NAGY ET AL. 38. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 179: 721–724, 1999. 57. Brun RP, Tontonoz P, Forman BM, Ellis R, Chen J, Evans RM, Spiegelman BM. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev 10: 974 –984, 1996. 39. Benoit G, Altucci L, Flexor M, Ruchaud S, Lillehaug J, Raffelsberger W, Gronemeyer H, Lanotte M. RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J 18: 7011–7018, 1999. 58. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389: 753–758, 1997. 40. Benoit GR, Flexor M, Besancon F, Altucci L, Rossin A, Hillion J, Balajthy Z, Legres L, Segal-Bendirdjian E, Gronemeyer H, Lanotte M. Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells. Mol Endocrinol 15: 1154 –1169, 2001. 59. Budhu AS, Noy N. Direct channeling of retinoic acid between cellular retinoic acidbinding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to retinoic acid-induced growth arrest. Mol Cell Biol 22: 2632–2641, 2002. 41. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454: 470 – 477, 2008. 42. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, gut homing in the face of high levels of co-stimulation. J Exp Med 204: 1765–1774, 2007. 44. Bhalla AK, Amento EP, Krane SM. Differential effects of 1,25-dihydroxyvitamin D3 on human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. Cell Immunol 98: 311–322, 1986. 45. Bhatia M, Kirkland JB, Meckling-Gill KA. M-CSF and 1,25 dihydroxy vitamin D3 synergize with 12-O-tetradecanoylphorbol-13-acetate to induce macrophage differentiation in acute promyelocytic leukemia NB4 cells. Leukemia 8: 1744 –1749, 1994. 46. Bjorkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci USA 91: 8592– 8596, 1994. 47. Bjorkhem I, Leitersdorf E. Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans. Trends Endocrinol Metab 11: 180 –183, 2000. 48. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22: 347–351, 1999. 49. Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem 38: 3146 –3155, 1995. 50. Bonder CS, Dickensheets HL, Finlay-Jones JJ, Donnelly RP, Hart PH. Involvement of the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of human monocyte and macrophage proinflammatory mediator production. J Immunol 160: 4048 – 4056, 1998. 51. Botling J, Oberg F, Torma H, Tuohimaa P, Blauer M, Nilsson K. Vitamin D3- and retinoic acid-induced monocytic differentiation: interactions between the endogenous vitamin D3 receptor, retinoic acid receptors, and retinoid X receptors in U-937 cells. Cell Growth Differ 7: 1239 –1249, 1996. 52. Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6: 137–143, 2007. 53. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Hayden MR. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22: 336 –345, 1999. 54. Brown G, Bunce CM, Rowlands DC, Williams GR. All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes. Leukemia 8: 806 – 815, 1994. 61. Burmester JK, Maeda N, DeLuca HF. Isolation and expression of rat 1,25-dihydroxyvitamin D3 receptor cDNA. Proc Natl Acad Sci USA 85: 1005–1009, 1988. 62. Burmester JK, Wiese RJ, Maeda N, DeLuca HF. Structure and regulation of the rat 1,25-dihydroxyvitamin D3 receptor. Proc Natl Acad Sci USA 85: 9499 –9502, 1988. 63. Bush TS, St Coeur M, Resendes KK, Rosmarin AG. GA-binding protein (GABP) and Sp1 are required, along with retinoid receptors, to mediate retinoic acid responsiveness of CD18 (beta 2 leukocyte integrin): a novel mechanism of transcriptional regulation in myeloid cells. Blood 101: 311–317, 2003. 64. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 266: 7779 –7783, 1991. 65. Cali JJ, Russell DW. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J Biol Chem 266: 7774 –7778, 1991. 66. Calleja C, Messaddeq N, Chapellier B, Yang H, Krezel W, Li M, Metzger D, Mascrez B, Ohta K, Kagechika H, Endo Y, Mark M, Ghyselinck NB, Chambon P. Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes. Genes Dev 20: 1525–1538, 2006. 67. Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC. Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 277: 39561–39565, 2002. 68. Carbone R, Botrugno OA, Ronzoni S, Insinga A, Di Croce L, Pelicci PG, Minucci S. Recruitment of the histone methyltransferase SUV39H1 and its role in the oncogenic properties of the leukemia-associated PML-retinoic acid receptor fusion protein. Mol Cell Biol 26: 1288 –1296, 2006. 69. Carrasco YR, Batista FD. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27: 160 –171, 2007. 70. Castrillo A, Diaz-Guerra MJ, Hortelano S, Martin-Sanz P, Bosca L. Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macrophages. Mol Cell Biol 20: 1692–1698, 2000. 71. Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, Tontonoz P. Liver X receptordependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem 278: 10443–10449, 2003. 72. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 12: 805– 816, 2003. 73. Castrillo A, Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu Rev Cell Dev Biol 20: 455– 480, 2004. 74. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940 –954, 1996. 75. Chang MD, Pollard JW, Khalili H, Goyert SM, Diamond B. Mouse placental macrophages have a decreased ability to present antigen. Proc Natl Acad Sci USA 90: 462– 466, 1993. 55. Brumbaugh PF, Haussler MR. 1Alpha,25-dihydroxyvitamin D3 receptor: competitive binding of vitamin D analogs. Life Sci 13: 1737–1746, 1973. 76. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7: 48 –52, 2001. 56. Brumbaugh PF, Haussler MR. Nuclear and cytoplasmic receptors for 1,25-dihydroxycholecalciferol in intestinal mucosa. Biochem Biophys Res Commun 51: 74 – 80, 1973. 77. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P. A PPAR gamma-LXR-ABCA1 path- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 775 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 43. Berer A, Stockl J, Majdic O, Wagner T, Kollars M, Lechner K, Geissler K, Oehler L. 1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. Exp Hematol 28: 575–583, 2000. 60. Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J 11: 1409 –1418, 1992. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES way in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7: 161–171, 2001. 78. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 294: 1866 –1870, 2001. 79. Chen KS, DeLuca HF. Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta 1263: 1–9, 1995. 80. Chen M, Beaven S, Tontonoz P. Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha. J Lipid Res 46: 2570 –2579, 2005. 81. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179: 1634 –1647, 2007. 83. Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 21: 372–377, 2001. 84. Chen ZP, Iyer J, Bourguet W, Held P, Mioskowski C, Lebeau L, Noy N, Chambon P, Gronemeyer H. Ligand- and DNA-induced dissociation of RXR tetramers. J Mol Biol 275: 55– 65, 1998. 85. Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, Wang W, Zu WY, Yao XZ, Ling BJ. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 78: 1413–1419, 1991. 86. Cheung DL, Hart PH, Vitti GF, Whitty GA, Hamilton JA. Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human monocytes. Immunology 71: 70 –75, 1990. 87. Chih DY, Chumakov AM, Park DJ, Silla AG, Koeffler HP. Modulation of mRNA expression of a novel human myeloid-selective CCAAT/enhancer binding protein gene (C/EBP epsilon). Blood 90: 2987–2994, 1997. 88. Chisholm JW, Hong J, Mills SA, Lawn RM. The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J Lipid Res 44: 2039 –2048, 2003. 89. Chung SW, Kang BY, Kim SH, Pak YK, Cho D, Trinchieri G, Kim TS. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J Biol Chem 275: 32681–32687, 2000. 90. Clohisy DR, Bar-Shavit Z, Chappel JC, Teitelbaum SL. 1,25-Dihydroxyvitamin D3 modulates bone marrow macrophage precursor proliferation and differentiation. Upregulation of the mannose receptor. J Biol Chem 262: 15922–15929, 1987. 91. Cohen MS, Mesler DE, Snipes RG, Gray TK. 1,25-Dihydroxyvitamin D3 activates secretion of hydrogen peroxide by human monocytes. J Immunol 136: 1049 –1053, 1986. 92. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, Plunket KD, Morgan DG, Beaudet EJ, Whitney KD, Kliewer SA, Willson TM. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45: 1963–1966, 2002. 98. Costet P, Lalanne F, Gerbod-Giannone MC, Molina JR, Fu X, Lund EG, Gudas LJ, Tall AR. Retinoic acid receptor-mediated induction of ABCA1 in macrophages. Mol Cell Biol 23: 7756 –7766, 2003. 99. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240 –28245, 2000. 100. Coutant F, Agaugue S, Perrin-Cocon L, Andre P, Lotteau V. Sensing environmental lipids by dendritic cell modulates its function. J Immunol 172: 54 – 60, 2004. 101. Coutant F, Perrin-Cocon L, Agaugue S, Delair T, Andre P, Lotteau V. Mature dendritic cell generation promoted by lysophosphatidylcholine. J Immunol 169: 1688 –1695, 2002. 102. Crisby M, Nilsson J, Kostulas V, Bjorkhem I, Diczfalusy U. Localization of sterol 27-hydroxylase immuno-reactivity in human atherosclerotic plaques. Biochim Biophys Acta 1344: 278 –285, 1997. 103. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55: 2945– 2950, 1987. 104. Cua DJ, Stohlman SA. In vivo effects of T helper cell type 2 cytokines on macrophage antigen-presenting cell induction of T helper subsets. J Immunol 159: 5834 –5840, 1997. 105. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3⫹ regulatory T cells: more of the same or a division of labor? Immunity 30: 626 – 635, 2009. 106. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3 involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 101: 252–262, 1998. 107. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H, Simon MC. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol 4: 1029 –1036, 2003. 108. Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259: 1739 –1742, 1993. 109. Darmanin S, Chen J, Zhao S, Cui H, Shirkoohi R, Kubo N, Kuge Y, Tamaki N, Nakagawa K, Hamada J, Moriuchi T, Kobayashi M. All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors. J Immunol 179: 4616 – 4625, 2007. 110. Davies SS, Pontsler AV, Marathe GK, Harrison KA, Murphy RC, Hinshaw JC, Prestwich GD, Hilaire AS, Prescott SM, Zimmerman GA, McIntyre TM. Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists. J Biol Chem 276: 16015–16023, 2001. 111. De Gentile A, Toubert ME, Dubois C, Krawice I, Schlageter MH, Balitrand N, Castaigne S, Degos L, Rain JD, Najean Y. Induction of high-affinity GM-CSF receptors during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia 8: 1758 –1762, 1994. 112. De Luca LM. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J 5: 2924 –2933, 1991. 93. Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16: 1896 –1905, 2002. 113. De The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347: 558 –561, 1990. 94. Colston KW, Evans IM, Spelsberg TC, MacIntyre I. Feedback regulation of vitamin D metabolism by 1,25-dihydroxycholecalciferol. Biochem J 164: 83– 89, 1977. 114. De The H, Marchio A, Tiollais P, Dejean A. Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes. EMBO J 8: 429 – 433, 1989. 95. Conesa-Botella A, Mathieu C, Colebunders R, Moreno-Reyes R, van Etten E, Lynen L, Kestens L. Is vitamin D deficiency involved in the immune reconstitution inflammatory syndrome? AIDS Res Ther 6: 4, 2009. 115. De The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343: 177–180, 1990. 96. Cools N, Ponsaerts P, Van Tendeloo VF, Berneman ZN. Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T cells. J Leukoc Biol 82: 1365–1374, 2007. 116. De Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290: 2140 –2144, 2000. 776 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 82. Chen Y, Green SR, Ho J, Li A, Almazan F, Quehenberger O. The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor gamma ligands. Biochem Biophys Res Commun 332: 188 –193, 2005. 97. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103⫹ DCs induces Foxp3⫹ regulatory T cells via a TGF- and retinoic acid dependent mechanism. J Exp Med 204: 1757–1764, 2007. NAGY ET AL. 117. DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS. Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci USA 98: 1477–1482, 2001. 118. Defacque H, Commes T, Legouffe E, Sevilla C, Rossi JF, Rochette-Egly C, Marti J. Expression of retinoid X receptor alpha is increased upon monocytic cell differentiation. Biochem Biophys Res Commun 220: 315–322, 1996. 119. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80: 1689S–1696S, 2004. 120. Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest 118: 956 –964, 2008. 121. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8: 1086 –1094, 2007. 123. Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J. Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 193: 827– 838, 2001. 124. Desvergne B, Michalik L, Wahli W. Transcriptional regulation of metabolism. Physiol Rev 86: 465–514, 2006. 125. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295: 1079 –1082, 2002. 126. Dong X, Craig T, Xing N, Bachman LA, Paya CV, Weih F, McKean DJ, Kumar R, Griffin MD. Direct transcriptional regulation of RelB by 1alpha,25-dihydroxyvitamin D3 and its analogs: physiologic and therapeutic implications for dendritic cell function. J Biol Chem 278: 49378 – 49385, 2003. 127. Douer D, Koeffler HP. Retinoic acid enhances growth of human early erythroid progenitor cells in vitro. J Clin Invest 69: 1039 –1041, 1982. 128. Drach J, McQueen T, Engel H, Andreeff M, Robertson KA, Collins SJ, Malavasi F, Mehta K. Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha. Cancer Res 54: 1746 –1752, 1994. 129. Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem 267: 4315– 4324, 2000. 130. Dunlop TW, Vaisanen S, Frank C, Molnar F, Sinkkonen L, Carlberg C. The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol 349: 248 –260, 2005. 137. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P, Delerive P, Maliszewski C, Capron M, Staels B, Moser M, Trottein F. Peroxisome proliferatoractivated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett 486: 261–266, 2000. 138. Fenton MJ, Buras JA, Donnelly RP. IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. J Immunol 149: 1283–1288, 1992. 139. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311: 83– 87, 2006. 140. Fontaine C, Rigamonti E, Nohara A, Gervois P, Teissier E, Fruchart JC, Staels B, Chinetti-Gbaguidi G. Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages. Circ Res 101: 40 – 49, 2007. 141. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxydelta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83: 803– 812, 1995. 142. Frankenberger M, Hauck RW, Frankenberger B, Haussinger K, Maier KL, Heyder J, Ziegler-Heitbrock HW. All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) in human bronchoalveolar lavage cells. Mol Med 7: 263–270, 2001. 143. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D metabolite. Nature 228: 764 –766, 1970. 144. Friedman AD. Transcriptional control of granulocyte and monocyte development. Oncogene 26: 6816 – 6828, 2007. 145. Friedman AD. Transcriptional regulation of granulocyte and monocyte development. Oncogene 21: 3377–3390, 2002. 146. Fritah A, Christian M, Parker MG. The metabolic coregulator RIP140: an update. Am J Physiol Endocrinol Metab 299: E335–E340, 2010. 147. Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of 25hydroxyvitamin D3–1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood 102: 3314 –3316, 2003. 148. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG. 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterolloaded cells. J Biol Chem 276: 38378 –38387, 2001. 149. Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 69: 1673–1676, 1972. 150. Gauzzi MC, Purificato C, Donato K, Jin Y, Wang L, Daniel KC, Maghazachi AA, Belardelli F, Adorini L, Gessani S. Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis. J Immunol 174: 270 –276, 2005. 131. Duprez E, Lillehaug JR, Gaub MP, Lanotte M. Differential changes of retinoid-Xreceptor (RXR alpha) and its RAR alpha and PML-RAR alpha partners induced by retinoic acid and cAMP distinguish maturation sensitive and resistant t(15;17) promyelocytic leukemia NB4 cells. Oncogene 12: 2443–2450, 1996. 151. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 10: 453– 460. 132. Dzhagalov I, Chambon P, He YW. Regulation of CD8⫹ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J Immunol 178: 2113–2121, 2007. 153. Geissmann F, Revy P, Brousse N, Lepelletier Y, Folli C, Durandy A, Chambon P, Dy M. Retinoids regulate survival and antigen presentation by immature dendritic cells. J Exp Med 198: 623– 634, 2003. 133. Ehrchen J, Helming L, Varga G, Pasche B, Loser K, Gunzer M, Sunderkotter C, Sorg C, Roth J, Lengeling A. Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major. FASEB J 21: 3208 –3218, 2007. 154. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H. International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58: 760 –772, 2006. 134. Elgueta R, Sepulveda FE, Vilches F, Vargas L, Mora JR, Bono MR, Rosemblatt M. Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells. J Immunol 180: 6501– 6507, 2008. 155. Gery S, Park DJ, Vuong PT, Virk RK, Muller CI, Hofmann WK, Koeffler HP. RTP801 is a novel retinoic acid-responsive gene associated with myeloid differentiation. Exp Hematol 35: 572–578, 2007. 135. Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T, Kato S, Matsumoto T. Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology 144: 5138 –5144, 2003. 156. Geyeregger R, Zeyda M, Bauer W, Kriehuber E, Saemann MD, Zlabinger GJ, Maurer D, Stulnig TM. Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin. Blood 109: 4288 – 4295, 2007. 152. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71– 82, 2003. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 777 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 122. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471: 220 –224, 2011. 136. Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD. CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51: 297–305, 2005. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 157. Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, Rosenfeld MG, Glass CK. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell 25: 57–70, 2007. 158. Gianni M, Terao M, Zanotta S, Barbui T, Rambaldi A, Garattini E. Retinoic acid and granulocyte colony-stimulating factor synergistically induce leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. Blood 83: 1909 –1921, 1994. 159. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature 330: 624 – 629, 1987. 160. Gilles S, Mariani V, Bryce M, Mueller MJ, Ring J, Jakob T, Pastore S, Behrendt H, Traidl-Hoffmann C. Pollen-derived E1-phytoprostanes signal via PPAR-gamma and NF-kappaB-dependent mechanisms. J Immunol 182: 6653– 6658, 2009. 161. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6: 44 –55, 2006. 162. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10: 365–376, 2010. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391: 815– 818, 1998. 179. Guerriero A, Langmuir PB, Spain LM, Scott EW. PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells. Blood 95: 879 – 885, 2000. 180. Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91: 2634 –2642, 1998. 181. Guilliams M, Crozat K, Henri S, Tamoutounour S, Grenot P, Devilard E, de Bovis B, Alexopoulou L, Dalod M, Malissen B. Skin-draining lymph nodes contain dermisderived CD103(⫺) dendritic cells that constitutively produce retinoic acid and induce Foxp3(⫹) regulatory T cells. Blood 115: 1958 –1968, 2010. 182. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol 4: 24 –34, 2004. 164. Goerdt S, Kolde G, Bonsmann G, Hamann K, Czarnetzki B, Andreesen R, Luger T, Sorg C. Immunohistochemical comparison of cutaneous histiocytoses and related skin disorders: diagnostic and histogenetic relevance of MS-1 high molecular weight protein expression. J Pathol 170: 421– 427, 1993. 184. Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW, Naik S, Wohlfert EA, Chou DB, Oldenhove G, Robinson M, Grigg ME, Kastenmayer R, Schwartzberg PL, Belkaid Y. Essential role for retinoic acid in the promotion of CD4(⫹) T cell effector responses via retinoic acid receptor alpha. Immunity 34: 435– 447, 2011. 165. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigenpresenting cells. Immunity 10: 137–142, 1999. 185. Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 152: 3282–3293, 1994. 166. Gogolak P, Rethi B, Szatmari I, Lanyi A, Dezso B, Nagy L, Rajnavolgyi E. Differentiation of CD1a- and CD1a⫹ monocyte-derived dendritic cells is biased by lipid environment and PPARgamma. Blood 109: 643– 652, 2007. 167. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19: 1067–1077, 2005. 168. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 3: 23–35, 2003. 169. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953–964, 2005. 170. Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, Tonnel AB, Trottein F. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur J Immunol 31: 2857–2865, 2001. 186. Hammad H, de Heer HJ, Soullie T, Angeli V, Trottein F, Hoogsteden HC, Lambrecht BN. Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. Am J Pathol 164: 263–271, 2004. 187. Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Forster R, Pabst O. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J Exp Med 205: 2483–2490, 2008. 188. Han KH, Chang MK, Boullier A, Green SR, Li A, Glass CK, Quehenberger O. Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma. J Clin Invest 106: 793– 802, 2000. 189. Han S, Sidell N. Peroxisome-proliferator-activated-receptor gamma (PPARgamma) independent induction of CD36 in THP-1 monocytes by retinoic acid. Immunology 106: 53–59, 2002. 171. Gottfried E, Rehli M, Hahn J, Holler E, Andreesen R, Kreutz M. Monocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite. Biochem Biophys Res Commun 349: 209 –213, 2006. 190. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6: 508 –519, 2006. 172. Goyette P, Feng Chen C, Wang W, Seguin F, Lohnes D. Characterization of retinoic acid receptor-deficient keratinocytes. J Biol Chem 275: 16497–16505, 2000. 191. Hartwell D, Hassager C, Christiansen C. Effect of vitamin D2 and vitamin D3 on the serum concentrations of 1,25(OH)2D2, 1,25(OH)2D3 in normal subjects. Acta Endocrinol 115: 378 –384, 1987. 173. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, Schledzewski K, Goerdt S. Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol 53: 386 – 392, 2001. 174. Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277: 34182–34190, 2002. 175. Gresham GA, Howard AN. The histogenesis of the atherosclerotic “fatty streak.” J Atheroscler Res 1: 413– 416, 1961. 176. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptordependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 98: 6800 – 6805, 2001. 177. Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 270: 701–708, 2000. 178. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG. 778 192. Haunerland NH, Spener F. Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43: 328 –349, 2004. 193. He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP. Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet 18: 126 –135, 1998. 194. Helming L, Bose J, Ehrchen J, Schiebe S, Frahm T, Geffers R, Probst-Kepper M, Balling R, Lengeling A. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood 106: 4351– 4358, 2005. 195. Henrich VC, Sliter TJ, Lubahn DB, MacIntyre A, Gilbert LI. A steroid/thyroid hormone receptor superfamily member in Drosophila melanogaster that shares extensive sequence similarity with a mammalian homologue. Nucleic Acids Res 18: 4143– 4148, 1990. 196. Herbert KE, Walkley CR, Winkler IG, Hendy J, Olsen GH, Yuan YD, Chandraratna RA, Prince HM, Levesque JP, Purton LE. Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells. Transplantation 83: 375–384, 2007. 197. Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M. Macrophage PPAR gamma is required for normal skeletal muscle and Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 163. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell 104: 503–516, 2001. 183. Hakeda Y, Hiura K, Sato T, Okazaki R, Matsumoto T, Ogata E, Ishitani R, Kumegawa M. Existence of parathyroid hormone binding sites on murine hemopoietic blast cells. Biochem Biophys Res Commun 163: 1481–1486, 1989. NAGY ET AL. hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117: 1658 –1669, 2007. 198. Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 170: 5382–5390, 2003. 199. Hewison M, Zehnder D, Bland R, Stewart PM. 1alpha-Hydroxylase and the action of vitamin D. J Mol Endocrinol 25: 141–148, 2000. 200. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C. 9-Cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397– 406, 1992. 201. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4⫹CD44hi Cells. Immunity 29: 758 –770, 2008. 202. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 420: 333–336, 2002. 204. Holick MF. Vitamin D deficiency. N Engl J Med 357: 266 –281, 2007. 205. Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry 10: 2799 –2804, 1971. 206. Hollis BW, Horst RL. The assessment of circulating 25(OH)D and 1,25(OH)2D: where we are and where we are going. J Steroid Biochem Mol Biol 103: 473– 476, 2007. 207. Hollis BW, Kamerud JQ, Kurkowski A, Beaulieu J, Napoli JL. Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with 125I-labeled tracer. Clin Chem 42: 586 –592, 1996. 208. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39: 529 –533, 1993. 209. Hollis BW, Pittard WB 3rd. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab 59: 652– 657, 1984. 210. Homey B, Alenius H, Muller A, Soto H, Bowman EP, Yuan W, McEvoy L, Lauerma AI, Assmann T, Bunemann E, Lehto M, Wolff H, Yen D, Marxhausen H, To W, Sedgwick J, Ruzicka T, Lehmann P, Zlotnik A. CCL27-CCR10 interactions regulate T cellmediated skin inflammation. Nat Med 8: 157–165, 2002. 211. Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18: 461– 467, 2008. 220. Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 181: 5829 – 5835, 2008. 221. Im HJ, Craig TA, Pittelkow MR, Kumar R. Characterization of a novel hexameric repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that mediates 1alpha,25-dihydroxyvitamin D(3)-associated IEX-1 gene repression. Oncogene 21: 3706 –3714, 2002. 222. Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176: 1693–1702, 1992. 223. Ishimoto K, Tachibana K, Sumitomo M, Omote S, Hanano I, Yamasaki D, Watanabe Y, Tanaka T, Hamakubo T, Sakai J, Kodama T, Doi T. Identification of human low-density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha. FEBS Lett 580: 4929 – 4933, 2006. 224. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51: 2005–2011, 2002. 225. Itoh T, Fairall L, Amin A, Inab Y, Sznato A, Balint LB, Nagy L, Yamamoto K, Schwabe JWR. Structural basis for the activation of PPAR␥ by oxidized fatty acids. Nature Struct Mol Biol 15: 924 –931, 2008. 226. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 5: 987–995, 2004. 227. Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, Arinobu Y, Geary K, Zhang P, Dayaram T, Fenyus ML, Elf S, Chan S, Kastner P, Huettner CS, Murray R, Tenen DG, Akashi K. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106: 1590 –1600, 2005. 228. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21: 527–538, 2004. 229. Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, Berg PL, Davidsson T, Powrie F, Johansson-Lindbom B, Agace WW. Small intestinal CD103⫹ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med 205: 2139 –2149, 2008. 230. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci USA 96: 266 –271, 1999. 212. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860 – 867, 2006. 231. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728 –731, 1996. 213. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95: 2409 –2415, 1995. 232. Ji JD, Kim HJ, Rho YH, Choi SJ, Lee YH, Cheon HJ, Sohn J, Song GG. Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Delta12,14-prostaglandin J2. Rheumatology 44: 983–988, 2005. 214. Houck KA, Borchert KM, Hepler CD, Thomas JS, Bramlett KS, Michael LF, Burris TP. T0901317 is a dual LXR/FXR agonist. Mol Genet Metab 83: 184 –187, 2004. 233. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391: 82– 86, 1998. 215. Housley WJ, O’Conor CA, Nichols F, Puddington L, Lingenheld EG, Zhu L, Clark RB. PPARgamma regulates retinoic acid-mediated DC induction of Tregs. J Leukoc Biol 86: 293–301, 2009. 234. Jiang SJ, Campbell LA, Berry MW, Rosenfeld ME, Kuo CC. Retinoic acid prevents Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis. Microbes Infect 10: 1393–1397, 2008. 216. Hsu HC, Yang K, Kharbanda S, Clinton S, Datta R, Stone RM. All-trans retinoic acid induces monocyte growth factor receptor (c-fms) gene expression in HL-60 leukemia cells. Leukemia 7: 458 – 462, 1993. 235. Johnson BS, Chandraratna RA, Heyman RA, Allegretto EA, Mueller L, Collins SJ. Retinoid X receptor (RXR) agonist-induced activation of dominant-negative RXRretinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation. Mol Cell Biol 19: 3372–3382, 1999. 217. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 400: 378 –382, 1999. 218. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411: 599 – 603, 2001. 236. Johnson BS, Mueller L, Si J, Collins SJ. The cytokines IL-3 and GM-CSF regulate the transcriptional activity of retinoic acid receptors in different in vitro models of myeloid differentiation. Blood 99: 746 –753, 2002. 237. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119: 299 –309, 2004. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 779 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 203. Hofbauer LC, Heufelder AE. Vitamin D receptor knock-out mice: the expectational and the exceptional. Eur J Endocrinol 138: 372–373, 1998. 219. Hulten LM, Lindmark H, Diczfalusy U, Bjorkhem I, Ottosson M, Liu Y, Bondjers G, Wiklund O. Oxysterols present in atherosclerotic tissue decrease the expression of lipoprotein lipase messenger RNA in human monocyte-derived macrophages. J Clin Invest 97: 461– 468, 1996. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 238. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 9: 213–219, 2003. 239. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019 –11025, 2002. 240. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA 99: 7604 –7609, 2002. 241. Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66: 663– 674, 1991. 242. Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT, Takayama T, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T. Human CD14⫹ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. J Immunol 2009. 244. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116: 1494 –1505, 2006. 245. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH. Vitamin A metabolites induce gut-homing FoxP3⫹ regulatory T cells. J Immunol 179: 3724 –3733, 2007. 246. Kaplan DH. In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol 31: 446 – 451, 2010. 247. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3: 984 –993, 2003. 248. Kastner P, Chan S. Function of RARalpha during the maturation of neutrophils. Oncogene 20: 7178 –7185, 2001. 249. Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL, Dolle P, Chambon P. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78: 987–1003, 1994. 250. Kastner P, Lawrence HJ, Waltzinger C, Ghyselinck NB, Chambon P, Chan S. Positive and negative regulation of granulopoiesis by endogenous RARalpha. Blood 97: 1314 – 1320, 2001. 251. Kastner P, Mark M, Ghyselinck N, Krezel W, Dupe V, Grondona JM, Chambon P. Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124: 313–326, 1997. 252. Katz DR, Drzymala M, Turton JA, Hicks RM, Hunt R, Palmer L, Malkovsky M. Regulation of accessory cell function by retinoids in murine immune responses. Br J Exp Pathol 68: 343–350, 1987. 253. Kaufmann SH. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol 9: 705–712, 2008. 254. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278: 1626 –1629, 1997. 255. Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, Edwards PA. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem 276: 39438 –39447, 2001. 256. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 405: 421– 424, 2000. 257. Kersten S, Kelleher D, Chambon P, Gronemeyer H, Noy N. Retinoid X receptor alpha forms tetramers in solution. Proc Natl Acad Sci USA 92: 8645– 8649, 1995. 780 259. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, Romani N, Tripp CH, Douillard P, Leserman L, Kaiserlian D, Saeland S, Davoust J, Malissen B. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22: 643– 654, 2005. 260. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83: 813– 819, 1995. 261. Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature 355: 446 – 449, 1992. 262. Klotz L, Dani I, Edenhofer F, Nolden L, Evert B, Paul B, Kolanus W, Klockgether T, Knolle P, Diehl L. Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4⫹ T cell anergy. J Immunol 178: 2122–2131, 2007. 263. Klotz L, Hucke S, Thimm D, Classen S, Gaarz A, Schultze J, Edenhofer F, Kurts C, Klockgether T, Limmer A, Knolle P, Burgdorf S. Increased antigen cross-presentation but impaired cross-priming after activation of peroxisome proliferator-activated receptor gamma is mediated by up-regulation of B7H1. J Immunol 183: 129 –136, 2009. 264. Kodelja V, Muller C, Politz O, Hakij N, Orfanos CE, Goerdt S. Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern. J Immunol 160: 1411–1418, 1998. 265. Kodelja V, Muller C, Tenorio S, Schebesch C, Orfanos CE, Goerdt S. Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197: 478 – 493, 1997. 266. Koeffler HP, Amatruda T, Ikekawa N, Kobayashi Y, DeLuca HF. Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25dihydroxyvitamin D3 and its fluorinated analogues. Cancer Res 44: 5624 –5628, 1984. 267. Koren R, Ravid A, Rotem C, Shohami E, Liberman UA, Novogrodsky A. 1,25-Dihydroxyvitamin D3 enhances prostaglandin E2 production by monocytes. A mechanism which partially accounts for the antiproliferative effect of 1,25(OH)2D3 on lymphocytes. FEBS Lett 205: 113–116, 1986. 268. Kostrouch Z, Kostrouchova M, Love W, Jannini E, Piatigorsky J, Rall JE. Retinoic acid X receptor in the diploblast, Tripedalia cystophora. Proc Natl Acad Sci USA 95: 13442– 13447, 1998. 269. Kreutz M, Andreesen R, Krause SW, Szabo A, Ritz E, Reichel H. 1,25-Dihydroxyvitamin D3 production and vitamin D3 receptor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 82: 1300 – 1307, 1993. 270. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4: 597– 609, 1999. 271. Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld MG, Heyman RA, Glass CK. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature 371: 528 –531, 1994. 272. Labbaye C, Valtieri M, Testa U, Giampaolo A, Meccia E, Sterpetti P, Parolini I, Pelosi E, Bulgarini D, Cayre YE. Retinoic acid downmodulates erythroid differentiation and GATA1 expression in purified adult-progenitor culture. Blood 83: 651– 656, 1994. 273. Labrecque J, Allan D, Chambon P, Iscove NN, Lohnes D, Hoang T. Impaired granulocytic differentiation in vitro in hematopoietic cells lacking retinoic acid receptors alpha1 and gamma. Blood 92: 607– 615, 1998. 274. Laffitte BA, Joseph SB, Chen M, Castrillo A, Repa J, Wilpitz D, Mangelsdorf D, Tontonoz P. The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol Cell Biol 23: 2182–2191, 2003. 275. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P. Autoregulation of the human liver X receptor alpha promoter. Mol Cell Biol 21: 7558 – 7568, 2001. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 243. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 281: 26602–26614, 2006. 258. Kim SR, Lee KS, Park HS, Park SJ, Min KH, Jin SM, Lee YC. Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma. Mol Pharmacol 68: 1568 –1575, 2005. NAGY ET AL. 276. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98: 507–512, 2001. 294. Li J, King I, Sartorelli AC. Differentiation of WEHI-3B D⫹ myelomonocytic leukemia cells induced by ectopic expression of the protooncogene c-jun. Cell Growth Differ 5: 743–751, 1994. 277. Lagishetty V, Misharin AV, Liu NQ, Lisse TS, Chun RF, Ouyang Y, McLachlan SM, Adams JS, Hewison M. Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis. Endocrinology 151: 2423–2432, 2010. 295. Li Y, Bolten C, Bhat BG, Woodring-Dietz J, Li S, Prayaga SK, Xia C, Lala DS. Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol Endocrinol 16: 506 –514, 2002. 278. Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, Gantner BN, Dinner AR, Singh H. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126: 755–766, 2006. 296. Li Y, Zhang J, Schopfer FJ, Martynowski D, Garcia-Barrio MT, Kovach A, Suino-Powell K, Baker PR, Freeman BA, Chen YE, Xu HE. Molecular recognition of nitrated fatty acids by PPAR gamma. Nat Struct Mol Biol 15: 865– 867, 2008. 279. Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P, Geiger JD, Hanash S, Beretta L. Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics. J Biol Chem 276: 17920 –17931, 2001. 297. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94: 9831–9835, 1997. 280. Lee KS, Park SJ, Hwang PH, Yi HK, Song CH, Chai OH, Kim JS, Lee MK, Lee YC. PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB J 19: 1033–1035, 2005. 282. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, Feng D, Zhuo D, Stoeckert CJ Jr, Liu XS, Lazar MA. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev 22: 2941– 2952, 2008. 283. Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, Pfahl M. Retinoids selective for retinoid X receptor response pathways. Science 258: 1944 – 1946, 1992. 284. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272: 3137–3140, 1997. 285. Lehmann S, Paul C, Torma H. Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells. Clin Cancer Res 7: 367–373, 2001. 286. Lehrke I, Schaier M, Schade K, Morath C, Waldherr R, Ritz E, Wagner J. Retinoid receptor-specific agonists alleviate experimental glomerulonephritis. Am J Physiol Renal Physiol 282: F741–F751, 2002. 287. Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68: 377–395, 1992. 288. Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 134: 3032–3035, 1985. 289. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 Alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74: 657– 661, 1984. 290. Lemotte PK, Keidel S, Apfel CM. Phytanic acid is a retinoid X receptor ligand. Eur J Biochem 236: 328 –333, 1996. 291. Leslie DS, Dascher CC, Cembrola K, Townes MA, Hava DL, Hugendubler LC, Mueller E, Fox L, Roura-Mir C, Moody DB, Vincent MS, Gumperz JE, Illarionov PA, Besra GS, Reynolds CG, Brenner MB. Serum lipids regulate dendritic cell CD1 expression and function. Immunology 125: 289 –301, 2008. 292. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A. 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 355: 359 –361, 1992. 293. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106: 523–531, 2000. 299. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391: 811– 814, 1998. 300. Linehan SA, Martinez-Pomares L, Stahl PD, Gordon S. Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, mesangial cells, but not dendritic cells. J Exp Med 189: 1961–1972, 1999. 301. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M. In vivo analysis of dendritic cell development and homeostasis. Science 324: 392–397, 2009. 302. Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med 13: 117–124, 2007. 303. Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M, Vazirnia A, Zhang X, Steinmeyer A, Zugel U, Hollis BW, Cheng G, Modlin RL. Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS One 4: e5810, 2009. 304. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770 – 1773, 2006. 305. Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179: 2060 –2063, 2007. 306. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell 73: 643– 658, 1993. 307. Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120: 2723–2748, 1994. 308. Lord KA, Abdollahi A, Hoffman-Liebermann B, Liebermann DA. Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation. Mol Cell Biol 13: 841– 851, 1993. 309. Luo Y, Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 105: 513–520, 2000. 310. Luria A, Furlow JD. Spatiotemporal retinoid-X receptor activation detected in live vertebrate embryos. Proc Natl Acad Sci USA 101: 8987– 8992, 2004. 311. Lusis AJ. Atherosclerosis. Nature 407: 233–241, 2000. 312. Ma J, Chen T, Mandelin J, Ceponis A, Miller NE, Hukkanen M, Ma GF, Konttinen YT. Regulation of macrophage activation. Cell Mol Life Sci 60: 2334 –2346, 2003. 313. Mak PA, Kast-Woelbern HR, Anisfeld AM, Edwards PA. Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 43: 2037–2041, 2002. 314. Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P, Edwards PA. Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta. J Biol Chem 277: 31900 –31908, 2002. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 781 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 281. Lee SJ, Yang EK, Kim SG. Peroxisome proliferator-activated receptor-gamma and retinoic acid X receptor alpha represses the TGFbeta1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation. Mol Pharmacol 70: 415– 425, 2006. 298. Libby P. Inflammation in atherosclerosis. Nature 420: 868 – 874, 2002. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 315. Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T. Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem Biophys Res Commun 299: 916 –923, 2002. 335. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215, 1999. 316. Maly P, Thall A, Petryniak B, Rogers CE, Smith PL, Marks RM, Kelly RJ, Gersten KM, Cheng G, Saunders TL, Camper SA, Camphausen RT, Sullivan FX, Isogai Y, Hindsgaul O, von Andrian UH, Lowe JB. The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86: 643– 653, 1996. 336. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, Mark M. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120: 2749 –2771, 1994. 317. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6: 329 –344, 1992. 318. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell 83: 841– 850, 1995. 319. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345: 224 –229, 1990. 321. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, Pulendran B. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329: 849 – 853, 2010. 322. Marathe C, Bradley MN, Hong C, Chao L, Wilpitz D, Salazar J, Tontonoz P. Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma⫺/⫺, PPARdelta⫺/⫺, PPARgammadelta⫺/⫺, or LXRalphabeta⫺/⫺ bone marrow. J Lipid Res 50: 214 –224, 2009. 323. Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during embryonic development. Nucl Recept Signal 7: e002, 2009. 324. Martinez-Pomares L, Gordon S. Antigen presentation the macrophage way. Cell 131: 641– 643, 2007. 325. Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol 19: 546 –551, 1999. 326. Mathieu C, Adorini L. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 8: 174 –179, 2002. 338. Meunier L, Bohjanen K, Voorhees JJ, Cooper KD. Retinoic acid upregulates human Langerhans cell antigen presentation and surface expression of HLA-DR and CD11c, a beta 2 integrin critically involved in T-cell activation. J Invest Dermatol 103: 775–779, 1994. 339. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, Saez E. The nuclear receptor LXR is a glucose sensor. Nature 445: 219 –223, 2007. 340. Mitro N, Vargas L, Romeo R, Koder A, Saez E. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett 581: 1721–1726, 2007. 341. Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH. Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations. Arch Neurol 59: 527–529, 2002. 342. Mohty M, Morbelli S, Isnardon D, Sainty D, Arnoulet C, Gaugler B, Olive D. All-trans retinoic acid skews monocyte differentiation into interleukin-12-secreting dendriticlike cells. Br J Haematol 122: 829 – 836, 2003. 343. Molenaar R, Greuter M, van der Marel AP, Roozendaal R, Martin SF, Edele F, Huehn J, Forster R, O’Toole T, Jansen W, Eestermans IL, Kraal G, Mebius RE. Lymph node stromal cells support dendritic cell-induced gut-homing of T cells. J Immunol 183: 6395– 6402, 2009. 344. Molenaar R, Knippenberg M, Goverse G, Olivier BJ, de Vos AF, O’Toole T, Mebius RE. Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J Immunol 186: 1934 –1942, 2011. 345. Molteni V, Li X, Nabakka J, Liang F, Wityak J, Koder A, Vargas L, Romeo R, Mitro N, Mak PA, Seidel HM, Haslam JA, Chow D, Tuntland T, Spalding TA, Brock A, Bradley M, Castrillo A, Tontonoz P, Saez E. N-Acylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRbeta. J Med Chem 50: 4255– 4259, 2007. 327. Matikainen S, Ronni T, Hurme M, Pine R, Julkunen I. Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells. Blood 88: 114 –123, 1996. 346. Montemurro P, Barbuti G, Conese M, Gabriele S, Petio M, Colucci M, Semeraro N. Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase-induced extracellular proteolysis. Br J Haematol 107: 294 –299, 1999. 328. Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB, Weaver CT. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J Exp Med 206: 343–357, 2009. 347. Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS, Mortensen RM, Spiegelman BM, Freeman MW. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med 7: 41– 47, 2001. 329. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Wilson PW, Jacques P. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 125: 353–359, 1996. 348. Mora JR. Homing imprinting and immunomodulation in the gut: role of dendritic cells and retinoids. Inflamm Bowel Dis 14: 275–289, 2008. 330. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ, Maki RA. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15: 5647–5658, 1996. 331. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394 –397, 1997. 332. Meehan MA, Kerman RH, Lemire JM. 1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 140: 400 – 409, 1992. 333. Mehta K, McQueen T, Neamati N, Collins S, Andreeff M. Activation of retinoid receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells. Cell Growth Differ 7: 179 –186, 1996. 334. Mehta K, McQueen T, Tucker S, Pandita R, Aggarwal BB. Inhibition by all-transretinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages. J Leukoc Biol 55: 336 –342, 1994. 782 349. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157–1160, 2006. 350. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008. 351. Morales J, Homey B, Vicari AP, Hudak S, Oldham E, Hedrick J, Orozco R, Copeland NG, Jenkins NA, McEvoy LM, Zlotnik A. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci USA 96: 14470 – 14475, 1999. 352. Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7: 610 – 621, 2007. 353. Mosser DM. The many faces of macrophage activation. J Leukoc Biol 73: 209 –212, 2003. 354. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958 –969, 2008. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 320. Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, Rosenthal KM, Evavold BD, Pulendran B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med 15: 401– 409, 2009. 337. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 50: 72–77, 2004. NAGY ET AL. 355. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256 –260, 2007. 356. Mucida D, Pino-Lagos K, Kim G, Nowak E, Benson MJ, Kronenberg M, Noelle RJ, Cheroutre H. Retinoic acid can directly promote TGF-beta-mediated Foxp3(⫹) Treg cell conversion of naive T cells. Immunity 30: 471– 473, 2009. 357. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 107: 3330 –3338, 2006. 358. Mues B, Langer D, Zwadlo G, Sorg C. Phenotypic characterization of macrophages in human term placenta. Immunology 67: 303–307, 1989. 359. Mukherjee R, Davies PJ, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG, Boehm MF, Mondon CE, Nadzan AM, Paterniti JR Jr, Heyman RA. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386: 407– 410, 1997. 361. Munder M, Eichmann K, Moran JM, Centeno F, Soler G, Modolell M. Th1/Th2regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 163: 3771–3777, 1999. 362. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A. Vitamin D intake and incidence of multiple sclerosis. Neurology 62: 60 – 65, 2004. 374. Nakajima H, Kizaki M, Ueno H, Muto A, Takayama N, Matsushita H, Sonoda A, Ikeda Y. All-trans and 9-cis retinoic acid enhance 1,25-dihydroxyvitamin D3-induced monocytic differentiation of U937 cells. Leukoc Res 20: 665– 676, 1996. 375. Nakken B, Varga T, Szatmari I, Szeles L, Gyongyosi A, Illarionov PA, Dezso B, Gogolak P, Rajnavolgyi E, Nagy L. Peroxisome proliferator-activated receptor gamma-regulated cathepsin D is required for lipid antigen presentation by dendritic cells. J Immunol 187: 240 –247, 2011. 376. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell 134: 405– 415, 2008. 377. Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, Shih DM, Van Lenten BJ, Frank JS, Demer LL, Edwards PA, Fogelman AM. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 16: 831– 842, 1996. 378. Nencioni A, Grunebach F, Zobywlaski A, Denzlinger C, Brugger W, Brossart P. Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma. J Immunol 169: 1228 –1235, 2002. 379. Niederreither K, Subbarayan V, Dolle P, Chambon P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444 – 448, 1999. 363. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189: 1363–1372, 1999. 380. Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, Denissov S, Borgesen M, Francoijs KJ, Mandrup S, Stunnenberg HG. Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 22: 2953–2967, 2008. 364. Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S. The promoter of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)2D3. Biochem Biophys Res Commun 249: 11–16, 1998. 381. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 37: 113–119, 2008. 365. Na G, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Diaz M, Gallardo G, de Galarreta CR, Salazar J, Lopez F, Edwards P, Parks J, Andujar M, Tontonoz P, Castrillo A. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31: 245–258, 2009. 366. Na SY, Kang BY, Chung SW, Han SJ, Ma X, Trinchieri G, Im SY, Lee JW, Kim TS. Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem 274: 7674 –7680, 1999. 367. Nagy L, Saydak M, Shipley N, Lu S, Basilion JP, Yan ZH, Syka P, Chandraratna RA, Stein JP, Heyman RA, Davies PJ. Identification and characterization of a versatile retinoid response element (retinoic acid receptor response element-retinoid X receptor response element) in the mouse tissue transglutaminase gene promoter. J Biol Chem 271: 4355– 4365, 1996. 368. Nagy L, Schwabe JW. Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci 29: 317–324, 2004. 369. Nagy L, Thomazy VA, Chandraratna RA, Heyman RA, Davies PJ. Retinoid-regulated expression of BCL-2 and tissue transglutaminase during the differentiation and apoptosis of human myeloid leukemia (HL-60) cells. Leuk Res 20: 499 –505, 1996. 370. Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA, Davies PJ. Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 15: 3540 –3551, 1995. 371. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93: 229 –240, 1998. 372. Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, Carotta S, O’Keeffe M, Bahlo M, Papenfuss A, Kwak JY, Wu L, Shortman K. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8: 1217–1226, 2007. 373. Nakajima H, Kizaki M, Sonoda A, Mori S, Harigaya K, Ikeda Y. Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and 382. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395: 137–143, 1998. 383. Norbury CC. Drinking a lot is good for dendritic cells. Immunology 117: 443– 451, 2006. 384. Nozaki Y, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. Anti-inflammatory effect of all-trans-retinoic acid in inflammatory arthritis. Clin Immunol 119: 272–279, 2006. 385. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 38: 3–5, 2006. 386. Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4: 619 – 626, 2008. 387. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Eagle AR, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447: 1116 –1120, 2007. 388. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122: 707–721, 2005. 389. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411: 603– 606, 2001. 390. Ohoka Y, Yokota A, Takeuchi H, Maeda N, Iwata M. Retinoic acid-induced CCR9 expression requires transient TCR stimulation and cooperativity between NFATc2 and the retinoic acid receptor/retinoid X receptor complex. J Immunol 186: 733–744, 2011. 391. Ohta M, Okabe T, Ozawa K, Urabe A, Takaku F. 1 alpha,25-Dihydroxyvitamin D3 (calcitriol) stimulates proliferation of human circulating monocytes in vitro. FEBS Lett 185: 9 –13, 1985. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 783 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 360. Muller K, Heilmann C, Poulsen LK, Barington T, Bendtzen K. The role of monocytes and T cells in 1,25-dihydroxyvitamin D3 mediated inhibition of B cell function in vitro. Immunopharmacology 21: 121–128, 1991. granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells. Blood 84: 4107– 4115, 1994. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 392. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219 –246. 393. Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG. Identification of clonogenic common Flt3⫹M-CSFR⫹ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol 8: 1207–1216, 2007. 394. Orban TI, Apati A, Nemeth A, Varga N, Krizsik V, Schamberger A, Szebenyi K, Erdei Z, Varady G, Karaszi E, Homolya L, Nemet K, Gocza E, Miskey C, Mates L, Ivics Z, Izsvak Z, Sarkadi B. Applying a “double-feature” promoter to identify cardiomyocytes differentiated from human embryonic stem cells following transposon-based gene delivery. Stem Cells 27: 1077–1087, 2009. 412. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V. Vitamin D3 affects differentiation, maturation, and function of human monocytederived dendritic cells. J Immunol 164: 4443– 4451, 2000. 413. Pierce A, Heyworth CM, Nicholls SE, Spooncer E, Dexter TM, Lord JM, Owen-Lynch PJ, Wark G, Whetton AD. An activated protein kinase C alpha gives a differentiation signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating factor-stimulated signaling events. J Cell Biol 140: 1511–1518, 1998. 414. Pikuleva IA, Babiker A, Waterman MR, Bjorkhem I. Activities of recombinant human cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways. J Biol Chem 273: 18153–18160, 1998. 415. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085–2088, 1998. 396. Oro AE, McKeown M, Evans RM. Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor. Nature 347: 298 –301, 1990. 416. Portale AA, Halloran BP, Murphy MM, Morris RC Jr. Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans. J Clin Invest 77: 7–12, 1986. 397. Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16: 257–270, 2002. 417. Powell WS. 15-Deoxy-delta12,14-PGJ2: endogenous PPARgamma ligand or minor eicosanoid degradation product? J Clin Invest 112: 828 – 830, 2003. 398. Pai T, Chen Q, Zhang Y, Zolfaghari R, Ross AC. Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells. Biochemistry 46: 15198 –15207, 2007. 418. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci 29: 664 – 673, 2004. 399. Park DJ, Chumakov AM, Vuong PT, Chih DY, Gombart AF, Miller WH Jr, Koeffler HP. CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment. J Clin Invest 103: 1399 –1408, 1999. 400. Park EJ, Park SY, Joe EH, Jou I. 15d-PGJ2 and rosiglitazone suppress Janus kinaseSTAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. J Biol Chem 278: 14747–14752, 2003. 401. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437: 759 –763, 2005. 402. Pascual G, Glass CK. Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab 17: 321–327, 2006. 403. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol 11: 764 –768, 2001. 404. Peet DJ, Janowski BA, Mangelsdorf DJ. The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev 8: 571–575, 1998. 405. Penna G, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405–2411, 2000. 406. Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, Adorini L. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 178: 145–153, 2007. 407. Penna G, Giarratana N, Amuchastegui S, Mariani R, Daniel KC, Adorini L. Manipulating dendritic cells to induce regulatory T cells. Microbes Infect 7: 1033–1039, 2005. 408. Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L. Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4⫹Foxp3⫹ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106: 3490 –3497, 2005. 409. Perez de Lema G, Lucio-Cazana FJ, Molina A, Luckow B, Schmid H, de Wit C, Moreno-Manzano V, Banas B, Mampaso F, Schlondorff D. Retinoic acid treatment protects MRL/lpr lupus mice from the development of glomerular disease. Kidney Int 66: 1018 –1028, 2004. 419. Pryke AM, Duggan C, White CP, Posen S, Mason RS. Tumor necrosis factor-alpha induces vitamin D-1-hydroxylase activity in normal human alveolar macrophages. J Cell Physiol 142: 652– 656, 1990. 420. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci USA 84: 2995–2998, 1987. 421. Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F, Hassanzadeh Gh G. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 71: 597– 602, 2002. 422. Ralph AP, Kelly PM, Anstey NM. L-Arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis. Trends Microbiol 16: 336 –344, 2008. 423. Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11: 753–761, 1999. 424. Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7: 964 –974, 2007. 425. Rebe C, Raveneau M, Chevriaux A, Lakomy D, Sberna AL, Costa A, Bessede G, Athias A, Steinmetz E, Lobaccaro JM, Alves G, Menicacci A, Vachenc S, Solary E, Gambert P, Masson D. Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor alpha pathway increases the clearance of apoptotic cells by human macrophages. Circ Res 105: 393– 401, 2009. 426. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25-dihydroxyvitamin D3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 65: 1201–1209, 1987. 427. Reichel H, Koeffler HP, Bishop JE, Norman AW. 25-Hydroxyvitamin D3 metabolism by lipopolysaccharide-stimulated normal human macrophages. J Clin Endocrinol Metab 64: 1–9, 1987. 428. Reichel H, Koeffler HP, Norman AW. Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. J Biol Chem 262: 10931–10937, 1987. 429. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med 320: 980 –991, 1989. 430. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol 6: 476 – 483, 2006. 410. Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330: 444 – 450, 1987. 431. Reis e Sousa C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin Immunol 16: 27–34, 2004. 411. Phan TG, Grigorova I, Okada T, Cyster JG. Subcapsular encounter and complementdependent transport of immune complexes by lymph node B cells. Nat Immunol 8: 992–1000, 2007. 432. Reiss Y, Proudfoot AE, Power CA, Campbell JJ, Butcher EC. CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J Exp Med 194: 1541–1547, 2001. 784 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 395. Oritani K, Kaisho T, Nakajima K, Hirano T. Retinoic acid inhibits interleukin-6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6. Blood 80: 2298 –2305, 1992. NAGY ET AL. 433. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 277: 18793–18800, 2002. 434. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14: 2819 –2830, 2000. 435. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524 –1529, 2000. 436. Ricote M, Glass CK. PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta 1771: 926 –935, 2007. 437. Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 95: 7614 –7619, 1998. 439. Ricote M, Snyder CS, Leung HY, Chen J, Chien KR, Glass CK. Normal hematopoiesis after conditional targeting of RXRalpha in murine hematopoietic stem/progenitor cells. J Leukoc Biol 80: 850 – 861, 2006. 440. Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451–1455, 1984. 441. Rigby WF, Yirinec B, Oldershaw RL, Fanger MW. Comparison of the effects of 1,25dihydroxyvitamin D3 on T lymphocyte subpopulations. Eur J Immunol 17: 563–566, 1987. 442. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 66: 5314 –5321, 1998. 443. Rolph MS, Young TR, Shum BO, Gorgun CZ, Schmitz-Peiffer C, Ramshaw IA, Hotamisligil GS, Mackay CR. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. J Immunol 177: 7794 –7801, 2006. 444. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57: 159 –163, 1986. 445. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4: 611– 617, 1999. 446. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, Chavatte P, Farce A, Bulois P, Cortot A, Colombel JF, Desreumaux P. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201: 1205–1215, 2005. 447. Russell DW. Nuclear orphan receptors control cholesterol catabolism. Cell 97: 539 – 542, 1999. 448. Russell DW. Oxysterol biosynthetic enzymes. Biochim Biophys Acta 1529: 126 –135, 2000. 449. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22: 352–355, 1999. 450. Sabol SL, Brewer HB Jr, Santamarina-Fojo S. The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver. J Lipid Res 46: 2151–2167, 2005. 451. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, Zugel U, Steinmeyer A, Pollak A, Roth E, Boltz-Nitulescu G, Spittler A. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 36: 361–370, 2006. 453. Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma JX, Staehling-Hampton K, Trainor PA. RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev 21: 1113–1124, 2007. 454. Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 86: 1179 –1236, 2006. 455. Saurer L, McCullough KC, Summerfield A. In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J Immunol 179: 3504 –3514, 2007. 456. Savina A, Amigorena S. Phagocytosis and antigen presentation in dendritic cells. Immunol Rev 219: 143–156, 2007. 457. Schaier M, Lehrke I, Schade K, Morath C, Shimizu F, Kawachi H, Grone HJ, Ritz E, Wagner J. Isotretinoin alleviates renal damage in rat chronic glomerulonephritis. Kidney Int 60: 2222–2234, 2001. 458. Schaier M, Liebler S, Schade K, Shimizu F, Kawachi H, Grone HJ, Chandraratna R, Ritz E, Wagner J. Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat. J Mol Med 82: 116 –125, 2004. 459. Schebesch C, Kodelja V, Muller C, Hakij N, Bisson S, Orfanos CE, Goerdt S. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4⫹ T cells in vitro. Immunology 92: 478 – 486, 1997. 460. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118: 2992–3002, 2008. 461. Schild RL, Schaiff WT, Carlson MG, Cronbach EJ, Nelson DM, Sadovsky Y. The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids. J Clin Endocrinol Metab 87: 1105–1110, 2002. 462. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B. Role of LXRs in control of lipogenesis. Genes Dev 14: 2831–2838, 2000. 463. Schulz O, Pennington DJ, Hodivala-Dilke K, Febbraio M, Reis e Sousa C. CD36 or alphavbeta3 and alphavbeta5 integrins are not essential for MHC class I cross-presentation of cell-associated antigen by CD8 alpha⫹ murine dendritic cells. J Immunol 168: 6057– 6065, 2002. 464. Schwartz K, Lawn RM, Wade DP. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun 274: 794 – 802, 2000. 465. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265: 1573–1577, 1994. 466. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19: 59 –70, 2003. 467. Serhan CN, Devchand PR. Novel antiinflammatory targets for asthma. A role for PPARgamma? Am J Respir Cell Mol Biol 24: 658 – 661, 2001. 468. Sevov M, Elfineh L, Cavelier LB. Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochem Biophys Res Commun 348: 1047–1054, 2006. 469. Shah YM, Morimura K, Gonzalez FJ. Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis. Am J Physiol Gastrointest Liver Physiol 292: G657–G666, 2007. 470. Shiohara M, Dawson MI, Hobbs PD, Sawai N, Higuchi T, Koike K, Komiyama A, Koeffler HP. Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro. Blood 93: 2057–2066, 1999. 471. Shirakawa AK, Nagakubo D, Hieshima K, Nakayama T, Jin Z, Yoshie O. 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J Immunol 180: 2786 –2795, 2008. 472. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 116: 1793–1801, 2006. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 785 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 438. Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferator-activated receptor (PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol 66: 733–739, 1999. 452. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179: 1109 –1118, 1994. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES 473. Shulman AI, Mangelsdorf DJ. Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med 353: 604 – 615, 2005. 474. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8: 285–293, 2007. 475. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417: 750 –754, 2002. 476. Sly LM, Lopez M, Nauseef WM, Reiner NE. 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem 276: 35482– 35493, 2001. 493. Sunaga S, Maki K, Lagasse E, Blanco JC, Ozato K, Miyazaki J, Ikuta K. Myeloid differentiation is impaired in transgenic mice with targeted expression of a dominant negative form of retinoid X receptor beta. Br J Haematol 96: 19 –30, 1997. 494. Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW. CCL25 mediates the localization of recently activated CD8alphabeta(⫹) lymphocytes to the small-intestinal mucosa. J Clin Invest 110: 1113–1121, 2002. 495. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325: 612– 616, 2009. 496. Szabo E, Preis LH, Birrer MJ. Constitutive cJun expression induces partial macrophage differentiation in U-937 cells. Cell Growth Differ 5: 439 – 446, 1994. 497. Szanto A, Balint BL, Nagy ZS, Barta E, Dezso B, Pap A, Szeles L, Poliska S, Oros M, Evans RM, Barak Y, Schwabe J, Nagy L. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity 33: 699 –712, 2010. 478. Solomin L, Johansson CB, Zetterstrom RH, Bissonnette RP, Heyman RA, Olson L, Lendahl U, Frisen J, Perlmann T. Retinoid-X receptor signalling in the developing spinal cord. Nature 395: 398 – 402, 1998. 498. Szanto A, Benko S, Szatmari I, Balint BL, Furtos I, Ruhl R, Molnar S, Csiba L, Garuti R, Calandra S, Larsson H, Diczfalusy U, Nagy L. Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages. Mol Cell Biol 24: 8154 – 8166, 2004. 479. Song C, Hiipakka RA, Kokontis JM, Liao S. Ubiquitous receptor: structures, immunocytochemical localization, modulation of gene activation by receptors for retinoic acids and thyroid hormones. Ann NY Acad Sci 761: 38 – 49, 1995. 480. Sorg BL, Klan N, Seuter S, Dishart D, Radmark O, Habenicht A, Carlberg C, Werz O, Steinhilber D. Analysis of the 5-lipoxygenase promoter and characterization of a vitamin D receptor binding site. Biochim Biophys Acta 1761: 686 – 697, 2006. 481. Spears M, McSharry C, Thomson NC. Peroxisome proliferator-activated receptorgamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 36: 1494 –1504, 2006. 482. Standiford TJ, Kunkel SL, Liebler JM, Burdick MD, Gilbert AR, Strieter RM. Gene expression of macrophage inflammatory protein-1 alpha from human blood monocytes and alveolar macrophages is inhibited by interleukin-4. Am J Respir Cell Mol Biol 9: 192–198, 1993. 483. Steffensen KR, Schuster GU, Parini P, Holter E, Sadek CM, Cassel T, Eskild W, Gustafsson JA. Different regulation of the LXRalpha promoter activity by isoforms of CCAAT/enhancer-binding proteins. Biochem Biophys Res Commun 293: 1333–1340, 2002. 499. Szanto A, Nagy L. Retinoids potentiate peroxisome proliferator-activated receptor gamma action in differentiation, gene expression, lipid metabolic processes in developing myeloid cells. Mol Pharmacol 67: 1935–1943, 2005. 500. Szanto A, Nagy L. The many faces of PPARgamma: anti-inflammatory by any means? Immunobiology 213: 789 – 803, 2008. 501. Szanto A, Roszer T. Nuclear receptors in macrophages: a link between metabolism and inflammation. FEBS Lett 582: 106 –116, 2008. 502. Szatmari I, Gogolak P, Im JS, Dezso B, Rajnavolgyi E, Nagy L. Activation of PPARgamma specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity 21: 95–106, 2004. 503. Szatmari I, Nagy L. Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function. EMBO J 27: 2353–2362, 2008. 504. Szatmari I, Pap A, Ruhl R, Ma JX, Illarionov PA, Besra GS, Rajnavolgyi E, Dezso B, Nagy L. PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med 203: 2351–2362, 2006. 484. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176: 287–292, 1992. 505. Szatmari I, Torocsik D, Agostini M, Nagy T, Gurnell M, Barta E, Chatterjee K, Nagy L. PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110: 3271–3280, 2007. 485. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320: 915–924, 1989. 506. Szatmari I, Vamosi G, Brazda P, Balint BL, Benko S, Szeles L, Jeney V, Ozvegy-Laczka C, Szanto A, Barta E, Balla J, Sarkadi B, Nagy L. Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem 281: 23812–23823, 2006. 486. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 449: 419 – 426, 2007. 487. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, and tissue distribution. J Exp Med 137: 1142–1162, 1973. 488. Stock A, Booth S, Cerundolo V. Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans. J Exp Med 208: 761–773, 2011. 489. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL, Ghosh G, Glass CK. 15-Deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci USA 97: 4844 – 4849, 2000. 490. Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8: 1007–1018, 1994. 507. Szeles L, Keresztes G, Torocsik D, Balajthy Z, Krenacs L, Poliska S, Steinmeyer A, Zuegel U, Pruenster M, Rot A, Nagy L. 1,25-Dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype. J Immunol 182: 2074 –2083, 2009. 508. Szeles L, Poliska S, Nagy G, Szatmari I, Szanto A, Pap A, Lindstedt M, Santegoets SJ, Ruhl R, Dezso B, Nagy L. Research resource: transcriptome profiling of genes regulated by RXR and its permissive and nonpermissive partners in differentiating monocyte-derived dendritic cells. Mol Endocrinol 24: 2218 –2231, 2010. 509. Szondy Z, Sarang Z, Molnar P, Nemeth T, Piacentini M, Mastroberardino PG, Falasca L, Aeschlimann D, Kovacs J, Kiss I, Szegezdi E, Lakos G, Rajnavolgyi E, Birckbichler PJ, Melino G, Fesus L. Transglutaminase 2⫺/⫺ mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci USA 100: 7812–7817, 2003. 491. Sucov HM, Evans RM. Retinoic acid and retinoic acid receptors in development. Mol Neurobiol 10: 169 –184, 1995. 510. Takeda N, Manabe I, Shindo T, Iwata H, Iimuro S, Kagechika H, Shudo K, Nagai R. Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6. Arterioscler Thromb Vasc Biol 26: 1177–1183, 2006. 492. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007. 511. Takeuchi A, Reddy GS, Kobayashi T, Okano T, Park J, Sharma S. Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3mediated effects. J Immunol 160: 209 –218, 1998. 786 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 477. Smeland EB, Rusten L, Jacobsen SE, Skrede B, Blomhoff R, Wang MY, Funderud S, Kvalheim G, Blomhoff HK. All-trans retinoic acid directly inhibits granulocyte colonystimulating factor-induced proliferation of CD34⫹ human hematopoietic progenitor cells. Blood 84: 2940 –2945, 1994. NAGY ET AL. 512. Talukdar S, Hillgartner FB. The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0 – 901317. J Lipid Res 47: 2451–2461, 2006. 513. Tao Y, Yang Y, Wang W. Effect of all-trans-retinoic acid on the differentiation, maturation and functions of dendritic cells derived from cord blood monocytes. FEMS Immunol Med Microbiol 47: 444 – 450, 2006. 514. Tarrade A, Schoonjans K, Guibourdenche J, Bidart JM, Vidaud M, Auwerx J, RochetteEgly C, Evain-Brion D. PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology 142: 4504 – 4514, 2001. 515. Tarrade A, Schoonjans K, Pavan L, Auwerx J, Rochette-Egly C, Evain-Brion D, Fournier T. PPARgamma/RXRalpha heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 86: 5017–5024, 2001. 516. Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, Inaba T. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett 536: 6 –11, 2003. 518. Tocci A, Parolini I, Gabbianelli M, Testa U, Luchetti L, Samoggia P, Masella B, Russo G, Valtieri M, Peschle C. Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/ erythroid/monocytic to granulocytic differentiation program. Blood 88: 2878 –2888, 1996. 533. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13–24, 2006. 534. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 374: 334 –338, 2000. 535. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 97: 12097–12102, 2000. 536. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA. Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275: 14700 –14707, 2000. 537. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Vire E, Nomdedeu JF, Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, Di Croce L. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell 11: 513–525, 2007. 538. Villablanca EJ, Raccosta L, Zhou D, Fontana R, Maggioni D, Negro A, Sanvito F, Ponzoni M, Valentinis B, Bregni M, Prinetti A, Steffensen KR, Sonnino S, Gustafsson JA, Doglioni C, Bordignon C, Traversari C, Russo V. Tumor-mediated liver X receptoralpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat Med 16: 98 –105, 2010. 519. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissuespecific regulator of an adipocyte enhancer. Genes Dev 8: 1224 –1234, 1994. 539. Villablanca EJ, Zhou D, Valentinis B, Negro A, Raccosta L, Mauri L, Prinetti A, Sonnino S, Bordignon C, Traversari C, Russo V. Selected natural and synthetic retinoids impair CCR7- and CXCR4-dependent cell migration in vitro and in vivo. J Leukoc Biol 84: 871– 879, 2008. 520. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241–252, 1998. 540. Villadangos JA, Heath WR. Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm. Semin Immunol 17: 262–272, 2005. 521. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77: 289 –312, 2008. 522. Torocsik D, Barath M, Benko S, Szeles L, Dezso B, Poliska S, Hegyi Z, Homolya L, Szatmari I, Lanyi A, Nagy L. Activation of liver X receptor sensitizes human dendritic cells to inflammatory stimuli. J Immunol 184: 5456 –5465 2010. 523. Torocsik D, Szanto A, Nagy L. Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages. Mol Aspects Med 30: 134 –152, 2009. 524. Tsai S, Bartelmez S, Heyman R, Damm K, Evans R, Collins SJ. A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line. Genes Dev 6: 2258 –2269, 1992. 525. Tsai S, Collins SJ. A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage. Proc Natl Acad Sci USA 90: 7153–7157, 1993. 526. Turner RT, Bottemiller BL, Howard GA, Baylink DJ. In vitro metabolism of 25hydroxyvitamin D3 by isolated rat kidney cells. Proc Natl Acad Sci USA 77: 1537–1540, 1980. 527. Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, Sato S, Tsujimura T, Yamamoto M, Yokota Y, Kiyono H, Miyasaka M, Ishii KJ, Akira S. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Tolllike receptor 5. Nat Immunol 9: 769 –776, 2008. 528. Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65: 1255–1266, 1991. 529. Unanue ER. Antigen-presenting function of the macrophage. Annu Rev Immunol 2: 395– 428, 1984. 530. Uppenberg J, Svensson C, Jaki M, Bertilsson G, Jendeberg L, Berkenstam A. Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J Biol Chem 273: 31108 –31112, 1998. 531. Valledor AF, Hsu LC, Ogawa S, Sawka-Verhelle D, Karin M, Glass CK. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci USA 101: 17813–17818, 2004. 541. Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 7: 543–555, 2007. 542. Vivat-Hannah V, Bourguet W, Gottardis M, Gronemeyer H. Separation of retinoid X receptor homo- and heterodimerization functions. Mol Cell Biol 23: 7678 –7688, 2003. 543. Wada Y, Hisamatsu T, Kamada N, Okamoto S, Hibi T. Retinoic acid contributes to the induction of IL-12-hypoproducing dendritic cells. Inflamm Bowel Dis 2009. 544. Waku T, Shiraki T, Oyama T, Fujimoto Y, Maebara K, Kamiya N, Jingami H, Morikawa K. Structural insight into PPARgamma activation through covalent modification with endogenous fatty acids. J Mol Biol 385: 188 –199, 2009. 545. Walkley CR, Purton LE, Snelling HJ, Yuan YD, Nakajima H, Chambon P, Chandraratna RA, McArthur GA. Identification of the molecular requirements for an RAR alphamediated cell cycle arrest during granulocytic differentiation. Blood 103: 1286 –1295, 2004. 546. Wang K, Wang P, Shi J, Zhu X, He M, Jia X, Yang X, Qiu F, Jin W, Qian M, Fang H, Mi J, Xiao H, Minden M, Du Y, Chen Z, Zhang J. PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell 17: 186 –197, 2010. 547. Wang TT, Dabbas B, Laperriere D, Bitton AJ, Soualhine H, Tavera-Mendoza LE, Dionne S, Servant MJ, Bitton A, Seidman EG, Mader S, Behr MA, White JH. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem 285: 2227– 2231, 2010. 548. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173: 2909 –2912, 2004. 549. Wang X, Allen C, Ballow M. Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol 27: 193–200, 2007. 550. Wang X, Scott E, Sawyers CL, Friedman AD. C/EBPalpha bypasses granulocyte colony-stimulating factor signals to rapidly induce PU.1 gene expression, stimulate gran- Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 787 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 517. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291: 1544 –1547, 2001. 532. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 97: 93–101, 2005. NUCLEAR RECEPTORS IN DENDRITIC CELLS AND MACROPHAGES ulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts. Blood 94: 560 – 571, 1999. 551. Wang Y, Kurdi-Haidar B, Oram JF. LXR-mediated activation of macrophage stearoylCoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J Lipid Res 45: 972–980, 2004. 552. Wang Y, Zhang JJ, Dai W, Pike JW. Production of granulocyte colony-stimulating factor by THP-1 cells in response to retinoic acid and phorbol ester is mediated through the autocrine production of interleukin-1. Biochem Biophys Res Commun 225: 639 – 646, 1996. 553. Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP. Role of PML in cell growth and the retinoic acid pathway. Science 279: 1547–1551, 1998. 554. Ward JE, Tan X. Peroxisome proliferator activated receptor ligands as regulators of airway inflammation and remodelling in chronic lung disease. PPAR Res 2007: 14983, 2007. 556. Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 90: 1621–1625, 1998. 557. Weber C, Belge KU, von Hundelshausen P, Draude G, Steppich B, Mack M, Frankenberger M, Weber KS, Ziegler-Heitbrock HW. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 67: 699 –704, 2000. 558. Wei LN, Farooqui M, Hu X. Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140. J Biol Chem 276: 16107–16112, 2001. 559. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116: 115–124, 2006. 560. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796 – 1808, 2003. 561. Welch JS, Ricote M, Akiyama TE, Gonzalez FJ, Glass CK. PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci USA 100: 6712– 6717, 2003. 562. Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA. Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages. J Biol Chem 276: 43509 – 43515, 2001. 563. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355: 618 – 621, 2000. 564. Willy PJ, Mangelsdorf DJ. Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. Genes Dev 11: 289 –298, 1997. 565. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9: 1033–1045, 1995. 566. Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92: 189 –217, 1953. 567. Wilson NS, Villadangos JA. Lymphoid organ dendritic cells: beyond the Langerhans cells paradigm. Immunol Cell Biol 82: 91–98, 2004. 568. Winzler C, Rovere P, Rescigno M, Granucci F, Penna G, Adorini L, Zimmermann VS, Davoust J, Ricciardi-Castagnoli P. Maturation stages of mouse dendritic cells in growth factor-dependent long-term cultures. J Exp Med 185: 317–328, 1997. 788 570. Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity 26: 741–750, 2007. 571. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821–1830, 2003. 572. Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 38: 535–540, 1993. 573. Yamada H, Mizuno S, Ross AC, Sugawara I. Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis. J Nutr 137: 2696 –2700, 2007. 574. Yamanaka K, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, Mizutani H, Kupper TS. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol 121: 148 –157 e143, 2008. 575. Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, Tenen DG, Xanthopoulos KG. CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. Proc Natl Acad Sci USA 94: 6462– 6467, 1997. 576. Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395: 284 –288, 1998. 577. Yeh K, Silberman D, Gonzalez D, Riggs J. Complementary suppression of T cell activation by peritoneal macrophages and CTLA-4-Ig. Immunobiology 212: 1–10, 2007. 578. Yokota A, Takeuchi H, Maeda N, Ohoka Y, Kato C, Song SY, Iwata M. GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity. Int Immunol 21: 361–377, 2009. 579. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 21: 2991–3000, 2001. 580. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16: 391–396, 1997. 581. Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar MA. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 270: 23975–23983, 1995. 582. Yu L, Cao G, Repa J, Stangl H. Sterol regulation of scavenger receptor class B type I in macrophages. J Lipid Res 45: 889 – 899, 2004. 583. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci USA 105: 5207–5212, 2008. 584. Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin JM, Glass CK, Rosenfeld MG. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67: 1251–1266, 1991. 585. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, de Madariaga A, Domingo JC. 9-cis-Retinoic acid (9cRA), a retinoid X receptor (RXR) ligand, exerts immunosuppressive effects on dendritic cells by RXR-dependent activation: inhibition of peroxisome proliferator-activated receptor gamma blocks some of the 9cRA activities, precludes them to mature phenotype development. J Immunol 178: 6130 – 6139, 2007. 586. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, Diaz-Delfin J, de Madariaga MA, Domingo JC. Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR(gamma):RXR heterodimers: comparison with other polyunsaturated fatty acids. J Leukoc Biol 84: 1172– 1182, 2008. Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 555. Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324: 1385–1393, 1991. 569. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 118: e16 – e31, 2011. NAGY ET AL. 587. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325: 100 – 104, 2009. 591. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ. Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem 276: 43018 – 43024, 2001. 588. Zenke M, Hieronymus T. Towards an understanding of the transcription factor network of dendritic cell development. Trends Immunol 27: 140 –145, 2006. 592. Zhu J, Emerson SG. Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene 21: 3295–3313, 2002. 589. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 94: 569 –574, 1997. 590. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21: 853– 863, 2004. 593. Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher R, Waxman S, Enver T, Zelent A. Lineage restriction of the RARalpha gene expression in myeloid differentiation. Blood 98: 2563–2567, 2001. 594. Zhu L, Bisgaier CL, Aviram M, Newton RS. 9-Cis retinoic acid induces monocyte chemoattractant protein-1 secretion in human monocytic THP-1 cells. Arterioscler Thromb Vasc Biol 19: 2105–2111, 1999. 595. Ziegler-Heitbrock L. The CD14⫹ CD16⫹ blood monocytes: their role in infection and inflammation. J Leukoc Biol 81: 584 –592, 2007. Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on June 17, 2017 Physiol Rev • VOL 92 • APRIL 2012 • www.prv.org 789