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1521-0111/85/1/187–197$25.00 MOLECULAR PHARMACOLOGY Copyright ª 2013 by The American Society for Pharmacology and Experimental Therapeutics http://dx.doi.org/10.1124/mol.113.089573 Mol Pharmacol 85:187–197, January 2014 MINIREVIEW Polarization of the Innate Immune Response by Prostaglandin E2: A Puzzle of Receptors and Signals Mario Rodríguez, Esther Domingo, Cristina Municio, Yolanda Alvarez, Etzel Hugo, Nieves Fernández, and Mariano Sánchez Crespo Received September 11, 2013; accepted October 29, 2013 ABSTRACT Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E2 is the most abundant eicosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid receptors explain the difficulty encountered thus far to delineate the actual role of PGE2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca21and kinase-dependent activation of the cytosolic phospholipase A2, which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE2 is the most relevant product. Acting in an autocrine/ paracrine manner in macrophages, PGE2 induces a regulatory Introduction Eicosanoids are molecules derived from the oxidative metabolism of arachidonic acid (AA) that display numerous functions in organ homeostasis, including reproduction, hemostasis, acute inflammation, allergy, and pain. Their roles in inflammation at the site of pathogen entry and in IgEmediated reactions have been the focus of intensive study. More recently, it has been underscored that some eicosanoids This work was supported by the Plan Nacional de Salud y Farmacia [Grant SAF2010-15070]; Junta de Castilla y León [Grant CSI003A11-2]; Fundación Ramón Areces; and Red Temática de Investigación Cardiovascular from the Instituto de Salud Carlos III. dx.doi.org/10.1124/mol.113.089573. phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule LIGHT. PGE2 also stabilizes the suppressive function of myeloidderived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE2 is a central component of the inflammasomedependent induction of the eicosanoid storm that leads to massive loss of intravascular fluid, increases the mortality rate associated with coinfection by Candida ssp. and bacteria, and inhibits fungal phagocytosis. These effects have important consequences for the outcome of infections and the polarization of the immune response into the T helper cell types 2 and 17 and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases. are involved in the induction of the immune response after immunization, in the control of the activation of cytotoxic T lymphocyte and T helper (Th)1–mediated responses, and in the polarization of the immune response into Th2 and Th17 types. This diversity of actions makes it necessary to distinguish the effects of the different compounds and the environmental context in which they are produced. The first classification of eicosanoids stems from their production in either the lipoxygenase or the cyclooxygenase (COX) routes. Leukotrienes (LTs) and lipoxins are the main products of the lipoxygenase route, whereas thromboxanes and prostaglandins (PGs), with PGE2 as the most relevant element, are the main COX products involved in the inflammatory response. The function of ABBREVIATIONS: AA, arachidonic acid; BCL10, B-cell CLL/lymphoma 10; CARD9, caspase recruitment domain–containing protein 9; C/EBPb, CCAAT/enhancer-binding protein b; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; CREB, cAMP response element-binding protein; CRTC, CREB-regulated transcriptional coactivator; DC, dendritic cell; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin; EP, E prostanoid; EPAC, exchange protein activated by cAMP; IFN, interferon; IKK, IkB kinase; IL, interleukin; ITAM, immunoreceptor tyrosine-based activation motif; LPS, lipopolysaccharide; LT, leukotriene; MALT, mucose-associated lymphoid tissue; MAPK, mitogen-activated protein kinase; MDSC, myeloid-derived suppressor cell; MRT67307, N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide; NF-kB, nuclear factor kB; PAMP, pathogen-associated molecular pattern; PG, prostaglandin; PGES, prostaglandin E synthase; PKA, protein kinase A; PLC, phospholipase C; PRR, pattern recognition receptor; SIK, salt-inducible kinase; SYK, spleen tyrosine kinase; Th, T helper; TNFa, tumor necrosis factor-a; TORC, transducer of regulated CREB activity; TLR, Toll-like receptor; TRAF6, TNF receptor-associated factor-6. 187 Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 Department of Biochemistry and Molecular Biology, University of Valladolid, Valladolid, Spain (M.R., N.F.); and Institute of Biology and Molecular Genetics, Spanish National Research Council, Valladolid, Spain (E.D., C.M., Y.A., E.H., M.S.C.) 188 Rodríguez et al. stage in view of their capacity to interact with carbohydrate-based structural signatures expressed in microbial cell walls (see Geijtenbeek and Gringhuis, 2009, for a review). Signaling through Toll-like receptors (TLRs) leads to the activation of the mitogen-activated protein kinase (MAPK) cascade, IkB kinase (IKK), the nuclear factor kB (NF-kB) family of transcription factors, tank-binding kinase-1, and interferon (IFN) regulatory factors. Nucleotide-binding oligomerization domain family protein–like receptors are associated with IKK and inflammasome activation that allows the caspase1–mediated processing of prointerleukin (IL)-1b and pro–IL-18 to fully active proteins. The C-type lectin receptors may induce rapid responses because they contain immunoreceptor tyrosinebased activation motifs (ITAMs) that initiate a cascade of protein tyrosine phosphorylation reactions, phospholipase C (PLC)g activation, Ca21 mobilization, and IKK activation (Fig. 1). These features make signaling trough C-type lectin receptors a unique paradigm for a comprehensive study of eicosanoid production in the innate immune response. Fig. 1. The Candida paradigm for AA metabolism in DCs. The mannan and b-glucan components of the fungal cell wall are recognized by at least DC-SIGN, TLR2, dectin-1, the mannose receptor, and dectin-2. This gives rise to a series of signaling events implicating activation of SYK and Src families of tyrosine kinases. Both routes converge to activate PLCg and through the generation of diacylglycerol activate protein kinase C and MAPK cascades. Phosphorylation by MAPK and Ca2+-driven translocation of cPLA2a explain AA release from cell phospholipids. Activation of IkB kinases via MyD88 is a major factor explaining COX-2 and PGES induction. The CARD9/MALT/BCL10/TRAF6 complex is also involved in the activation of IkB kinases. This scheme has been constructed from the results reported by Suram et al. (2006, 2010), Valera et al. (2008), and Parti et al. (2010). DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; IRAK, interleukin-1 receptor-associated kinase; MAL, MyD88 adaptor-like; P-Y, phosphotyrosine; ptgs2, COX-2 gene; mpges1, microsomal prostaglandin E synthase-1 gene; TAK1, transforming growth factor-b–activated kinase-1. Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 LTs in the pathogenesis of the immediate hypersensitivity reactions elicited by allergens was most prominent from early studies in sensitized tissues (Kellaway and Trethewie, 1940), although at that time their chemical structure was unknown and more than 3 decades were needed to unambiguously characterize the activity that had been termed slow-reacting substance of anaphylaxis with the cysteinyl-LTs C4, D4, and E4 (Hammarström et al., 1979). Regarding the eicosanoids released from phagocytes, it was necessary to wait for the characterization of the receptors involved in the innate immune response to ascertain their actual role in inflammation. In fact, microbes have unique molecules termed pathogen-associated molecular patterns (PAMPs) that are recognized through pattern recognition receptors (PRRs) by the host innate immune system. The Toll-like receptor family and the nucleotide-binding oligomerization domain family protein–like receptors (see Casanova et al., 2011; Davis et al., 2011, respectively) are representative of what Janeway (1989) first called PRRs. More recently, C-lectin type receptors have enlarged the list of PRR and reached center Eicosanoids in Innate Immunity AA Release Is the Initial Step for Eicosanoid Production with an efficient substrate channeling model yielding AA for PGE2 synthesis at the early stages of microbial ingestion and explain the strong ability of b-glucans to fulfill the conditions associated with acute release of AA and production of COX products, in contrast to the effect of the TLR4 ligand LPS that only elicits robust PGE2 production after COX-2 induction. These findings also help explain the adjuvanticity associated with b-glucans that is being used for vaccine technology (Huang et al., 2010), since COX-2 activity is crucial for optimal antibody response, especially when vaccines are poorly immunogenic (Ryan et al., 2006). COX Enzymes and COX/Lipoxygenase Cross-Talk COX Enzymes. PGE2 is the predominant eicosanoid generated in response to TLR ligands, proinflammatory cytokines, and fungal-derived PAMPs. Central to PGE2 production are the COX enzymes, of which two isoforms exist that are similar in structure and catalytic activity. COX-1 is a constitutive enzyme that is coupled to the cPLA2a and paves the way for the production of PGE2 shortly after AA release. In contrast, COX-2 is an inducible enzyme regulated at the transcriptional level by an array of latent transcription factors that are activated downstream PRR engagement, namely NF-kB, cAMP response element-binding protein (CREB), CCAAT/enhancer-binding protein b (C/EBPb), and IFN regulatory factors. The relevance of post-transcriptional mechanisms that regulate mRNA stability and protein translation have been disclosed in recent years, and include several proteins and microRNA that modulate the decay rate of ptgs2 (the gene encoding COX-2) mRNA as well as two mechanisms of protein degradation. Identification of multiple mRNA regulatory elements present within the ptgs2 39-untranslated region was the first evidence suggesting that COX-2 might be regulated at a post-transcriptional level. This is explained by the presence of adenylate- and uridylate-rich elements that interact with adenylate and uridylate binding proteins, such as Hu antigen R, CUG triplet repeat–binding protein 2, T cell intracellular antigen 1, tristetraprolin, RNA-binding motif protein 3, and most recently Hsp70 (Kishor et al., 2013). With regard to microRNA, miR-16, miR-101, miR-199, miR-143, and miR-542-3p have shown to exhibit complementarity to adenylate- and uridylate-rich regions of ptgs2 that makes them suitable to alter their mRNA stability (Dixon et al., 2013). COX-2 protein has two independent routes of degradation: endoplasmic reticulum–associated degradation and substratedependent degradation. N-Glycosylation of Asn594 leads to entry of COX-2 into the endoplasmic reticulum–associated degradation pathway. The second COX-2 degradation process is substrate turnover dependent and is independent of N-glycosylation at Asn594 (Wada et al., 2009). Notably, COX-2 protein stability has been found to be enhanced by atorvastatin, which may influence dendritic cell (DC) function and counteract some of the untoward effects associated with sustained inhibition of COX-2 (Alvarez et al., 2009b). COX enzymes control PGE2 production by catalyzing the conversion of AA to PG in a two-step process. First, hydrogen is abstracted from carbon 13 of AA. Then a molecule of oxygen is added to carbons 11 and 9, thus provoking the cyclization and the addition of a second molecule of oxygen to carbon 15 to generate PGG2. Second, the hydroperoxide at carbon 15 of PGG2 is reduced to hydroxide by Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 PLA2 catalyzes the release of fatty acids from the sn-2 position of phospholipids. There are 22 genes encoding PLA2 in mammals that are usually grouped in three main types: the secreted PLA2, the intracellular group VI calcium-independent PLA2, and the group IV cytosolic PLA2. These structurally diverse enzymes carry out distinct functional roles (Dennis et al., 2011). The group IV cytosolic phospholipase A2 (cPLA2) family includes the cPLA2a, PLA2b, and cPLA2g isoforms. However, cPLA2a is the only PLA2 with specificity of AA and its primary function is to mediate agonist-induced release of AA. Because of its position as the upstream regulatory enzyme for initiating production of bioactive lipid mediators, cPLA2a has been considered a potentially important pharmacological target for the control of inflammatory responses. cPLA2a is subject to post-translational mechanisms of regulation to ensure that the levels of free AA are tightly controlled. These mechanisms include the following: 1) the phosphorylation of Ser505-cPLA2 by MAPK in the catalytic domain, which explains the increase of catalytic activity elicited by cell agonists; and 2) Ca21-induced translocation from the cytosol to membranes to allow cPLA2a interaction with phospholipid substrate. cPLA2 phosphorylation was initially related to MAPK of the extracellular signal-regulated kinase group (Lin et al., 1993), but the involvement of p38 MAPK was subsequently reported (Kramer et al., 1996). The agonist-stimulated translocation is explained by a N-terminal domain containing a 45 amino acid region with high homology with the Ca21-dependent phospholipid binding motif expressed in protein kinase C and PLC (Clark et al., 1991). Due to this structural feature, Ca 21 induces the translocation of cPLA2a from the cytoplasm to the Golgi, endoplasmic reticulum, and nuclear membrane. In keeping with this mechanism, only agonists creating a sustained Ca21 influx are capable of activating some elements of the AA cascade, such as the 5-lipoxygenase pathway, which are critically dependent on Ca21 (Buczynski et al., 2007). Since activation of TLR4 by lipopolysaccharide (LPS) fails to induce Ca21 transients directly but elicits prostaglandin production in the absence of lipoxygenase activation, a corollary to these findings is that acute release of AA and long-term production of COX-2 metabolites are under the control of different signaling pathways. Notably, PAMPs derived from the cellular wall of fungi, the main component of which are b(1,3)-glucans, have stood out as a class of stimuli able to activate both pathways. This has pathophysiological relevance to understanding the response of the host to infection by fungi such as Candida, Cryptococcus, Aspergillus, and Pneumocystis jirovecii. The recognition of b-glucans is carried out by the C-type lectin receptor dectin-1 (clec7a gene) (Brown et al., 2002), which contains an ITAM in its intracellular portion. Cross-linking of this receptor allows activation of tyrosine kinases, including spleen tyrosine kinase (SYK), tyrosine phosphorylation of PLCg, and the elevation of the intracellular levels of Ca21. In an elegant study stemming from the observation that cPLA2a exhibits calcium-dependent targeting to the endoplasmic reticulum, the site of COX localization, cPLA2a and COX-2 were found to colocalize to the forming phagosome in mouse peritoneal macrophages uptaking the fungal mimic zymosan (Girotti et al., 2004). These results fit well 189 190 Rodríguez et al. The Plasticity of Mononuclear Phagocytes Explains Distinct Patterns of PGE2 Production Opsonic and Nonopsonic Phagocytosis. Uptake of phagocytosable particles and signaling from PRR depend on both receptors that bind opsonic proteins and nonopsonic receptors. This is relevant to the engulfment of bacteria and fungi since these microbes can be coated by the complement factor 3–derived protein iC3b and by opsonic IgG class antibodies, which bind the integrin amb2/Mac-1 and FcgR receptors, respectively. Among nonopsonic receptors, scavenger receptors and C-type lectin receptors are of special relevance to directly recognize PAMP expressed on the microbe surface. Whereas the C-type lectin receptor dectin-1 recognizes b-glucans (Brown et al., 2002), dectin-2 recognizes a-mannans (Sato et al., 2006), and DC-specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN) recognizes N-linked mannans (Cambi et al., 2008). The mannose receptor recognizes terminal mannose and fucose residues, but its ability to modulate cellular activation has not been completely characterized (Martinez-Pomares, 2012). The combinatorial usage of receptors for b-glucans and a-mannans makes it possible an efficient recognition of pathogen dimorphic fungi since their cell wall contains an external layer made up of mannose polymers and an underlying layer of b-glucans. Cross-linking of opsonic receptors and the nonopsonic receptors dectin-1 and dectin-2 allows the recruitment of nonreceptor tyrosine kinases to the ITAMs expressed either in the intracellular portion of the receptor or in adaptor proteins, thus activating a cell signaling cascade involving protein tyrosine phosphorylation reactions, PLCg activation, Ca21 mobilization, and IKK activation. This diversity of receptors explains why signals elicited by a receptor may be balanced by concomitant signals induced by associated PAMPs on the same microbe or from the environment. In fact, the formation of the so-called phagocytic synapse is a pivotal element to define the degree of response of the host to the invading microbe, because recognition of PAMPs in a particulate state is a critical checkpoint for scaling the microbial threat versus the single recognition of soluble PAMPs (Blander and Sander, 2012). Notably, the construction of this general paradigm for tailoring the host responses stems from studies carried out with large b-glucan complexes, in which the exclusion of inhibitory phosphatases from the phagocytic synapse was a key element to start dectin-1– coupled signaling (Goodridge et al., 2011). The Different Macrophage Populations. Classic distinction between macrophage types includes the type M1 inflammatory macrophage and the M2 regulatory macrophage (see Sica and Mantovani, 2012 for a review). Peripheral blood monocytes cultured in the presence of serum, a source of macrophase colony-stimulating factor but not granulocyte macrophage colony-stimulating factor (Vogt and Nathan, 2011), are considered nonpolarized macrophages (M0 type), whereas the addition of different cytokine cocktails elicits polarization versus the M1 or M2 type. For instance, the M1 type is induced by IFN-g and LPS, and the M2 type is induced by IL-4 and IL-13. The ability of macrophages to produce eicosanoids in response to some PAMPs is strongly dependent on the type of polarization achieved and the ensuing pattern of receptor expression. A central role for macrophage-derived PGE2 in the induction of Th2 type immune responses has been reported during the processing of particulate crystal-like materials like alum and silica through a mechanism regulated by SYK and p38 MAPK. Under these conditions, the production of PGE2 depends on receptor-independent particle uptake and signaling from phagolysosomes, rather than on the engagement of cell membrane receptors, and may occur in the absence of inflammasome activation and IL-1b production (Kuroda et al., 2011). These findings are reminiscent of the response to other crystals such as sodium monourate particles (Kool et al., 2011) and hemozoin (Shio et al., 2009), and also agree with the reported activation of SYK by receptorindependent, direct membrane binding of monosodium urate crystals in DCs (Ng et al., 2008). These results are in keeping with the notion that particulate PAMPs are more active than soluble PAMPs for scaling microbial threat and are relevant to understand the inflammation induced by microcrystals. In addition, they underscore the complexity of the process of recognition of particles bearing PAMPs, which may include receptor dependent and independent mechanisms, and is influenced by receptor expression, the state of differentiation of the cell, and the presence of molecules that affect receptor function. Attempts to correlate the state of macrophage differentiation with eicosanoid release have steadily shown a predominant production of PGE2 and PGD2 and a varying pattern of response dependent on the presence of costimulatory substances. For instance, growth factors such as macrophase colony-stimulating factor and granulocyte macrophage Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 the peroxidase active site of COX to produce PGH2. PGH2 can be converted to PGD2, PGE2, PGF2a, prostacyclin, or thromboxane A2 by specific isomerases. PGE2 can be produced by three types of prostaglandin E synthases (PGES): one cytosolic (cPGES) and two membrane-associated (microsomal PGES-1 and -2). mPGES-1 is induced by the same stimuli that induce COX-2. On this basis, the combined induction of both COX-2 and mPGES-1 by proinflammatory stimuli explains the efficient conversion of AA into PGE2. COX/5-Lipoxygenase Cross-Talk. Cross-talk between the 5-lipoxygenase route and the COX pathways was observed in early studies by showing a widespread inhibitory effect of PG on LT production. In addition to the marked effect of PGE2 in DCs by inhibiting the expression of the 5-lipoxygenase–activating protein that is required for the activity of 5-lipoxygenase (Harizi et al., 2003), recent studies have disclosed new molecular targets by showing that phosphorylation of cPLA2a enhances its catalytic activity, whereas phosphorylation of LTC4 synthase is inhibitory. In a detailed study using zymosan as a stimulus, inhibition of LTC4 synthase was preceded by the production of PGE2 and abolished by aspirin treatment. This effect was associated with activation of several types of receptors for PGE2, the major downstream signaling of which were protein kinase A (PKA)–dependent phosphorylation reactions (Esser et al., 2011). A corollary to these findings is that when COX routes are operative, tissues possess a negative feedback mechanism to control the 5-lipoxygenase route. In the particular case of the lung, where PGE2 exerts anti-inflammatory effects and LTs drive inflammation, these findings provide a mechanistic explanation for two relevant clinical situations in asthma patients: the exacerbation of symptoms associated with aspirin intolerance and the risks conferred by fungal exposure in patients treated with high doses of nonsteroidal anti-inflammatory drugs. Eicosanoids in Innate Immunity expressed on the surface of polymorphonuclears, monocytes, and DCs, but DCs show the most robust responses. These differential responses might be explained by several mechanisms: 1) expression in some myeloid cell types of an inhibitor (e.g., tetraspanin CD37) that restricts dectin-1–CARD9 (caspase recruitment domain–containing protein 9) signaling (Goodridge et al., 2009); 2) gain of function of DCs by differentiation-induced expression of a receptor cooperating with dectin-1; and 3) induction along the process of differentiation of C-lectin receptor isoforms supporting productive binding. The last two mechanisms seem most likely in view of the high level of alternative exon splicing observed in dectin-1 and the current notion that zymosan-induced AA requires cooperation with other C-type lectin receptors, such as DC-SIGN, the expression of which is enhanced during the differentiation of monocytes into DCs (Domínguez-Soto et al., 2011). Altogether, these data indicate that cooperative binding of particulate b-glucans and mannans to C-type lectin receptors explains the activation of a cPLA2adependent route for AA release in DCs. Likewise, two different routes are involved in the kB-driven induction of COX-2 and the delayed production of PGE2 produced by zymosan, the CARD9/mucose-associated lymphoid tissue (MALT)/B-cell CLL/lymphoma 10 (BCL10)/TNF receptorassociated factor-6 (TRAF6) complex triggered by dectin-1 (Hara et al., 2007; LeibundGut-Landmann et al., 2007) and TLR2-dependent activation of IkB kinases (Brown et al., 2003; Gantner et al., 2003). The Candida Paradigm for AA Release. The fungal mimic zymosan has been used for many decades as a relevant stimulus to study complement activation, phagocytosis, and local inflammatory responses. On this basis, the results observed using zymosan as a stimulus can be translated into the context of clinical infection by fungi. This has been confirmed in models using Candida and macrophages from engineered mice to address AA release and PGE2 production. Reports from the Leslie laboratory (Suram et al., 2006, 2010; Parti et al., 2010) demonstrated that deletion of dectin-1 decreases the release of AA elicited by Candida albicans by approximately 60%. MyD882/2 macrophages stimulated for 1 hour with C. albicans released approximately 50% less AA than wild-type cells. In contrast, wild-type and MyD882/2 macrophages released similar amounts of AA in response to particulate b-glucan. The upregulation of COX-2 6 hours after adding C. albicans was almost completely ablated in MyD882/2 peritoneal macrophages, and the production of PGE2, PGI2, and LTC4 at 6 hours was reduced by 80–90% (Suram et al., 2006). These results suggest a major role for dectin-1 in the early release of AA and of TLR2, the action of which depends on the MyD88 adaptor, in the activation of kB-dependent transcription and COX-2 expression in the late phase of eicosanoid production (Fig. 1). The translation of this paradigm to clinical settings is especially relevant to understand the outcome of polymicrobial infections such as peritonitis, in which Candida spp. accompanies either Gram-positive or Gram-negative bacteria. Whereas monomicrobial infection is nonlethal, coinfection with the same doses leads to a 40% mortality rate and increases the microbial burden in the kidney and spleen. Notably, coinfection is associated with a synergistic production of PGE2 and blockade of the COX routes prevents mortality (Peters and Noverr, 2013). A sound explanation for the molecular mechanism whereby PGE2 leads to an immunocompromised state during Candida spp. infection Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 colony-stimulating factor elicit profound changes on the expression of receptors such as DC-SIGN and the dectin-1 B isoform, that is, the isoform displaying the most efficient productive binding to b-glucans (Rosas et al., 2008; Municio et al., 2013). Macrophages cultured in the presence of human serum show a high sensitivity to LPS as judged from a rapid induction of COX-2 and a high production of PGE2. In contrast, particulate zymosan, an extract of the Saccharomyces cerevisiae cell wall mainly composed of b-glucans, only induces COX-2 expression several hours after particle uptake (Municio et al., 2013). This putative phagolysosomal route of PGE2 production is synergistically enhanced by low concentrations of LPS, which agrees with the results observed with crystal-like materials (Kuroda et al., 2011). These findings are relevant to vaccine technology, since the release of PGE2 under these conditions helps explain the adjuvant effect of alum, one of the few approved adjuvants for use in humans, and maybe of b-glucans as well (Huang et al., 2010). The response of the macrophages is also influenced by their origin. For instance, peritoneal macrophages readily respond to bacterial products, whereas this response is less pronounced or even absent in bone marrow– derived macrophages. From a pathophysiological point of view, this is most evident in the response termed eicosanoid storm observed in response to bacterial toxins, where systemic inflammasome-dependent activation of cPLA2 and COX-1 in peritoneal macrophages by intraperitoneal injection of flagellin leads to a rapid loss of intravascular fluid, hemoconcentration, hypothermia, and death, which is not observed in mice deficient in COX-1 (von Moltke et al., 2012). DCs. DCs are professional antigen-presenting cells that bridge the innate and the adaptive immune response due to their ability to stimulate naive T cells and initiate immune responses through the activation of Th cells. PGE2 is a key factor for the surface expression of CCR7 and the ensuing acquisition of responsiveness to CCL21 and CCL19, which are expressed in lymphatic vessels and the T cell areas of lymph nodes (Scandella et al., 2002; Kabashima et al., 2003). Mice lacking CCR7 fail to migrate into draining lymph nodes; congruent with this pivotal function of PGE2, failure of DCs to produce PGE2 has been considered a major obstacle for the successful application of DCs in therapy (Thurnher et al., 2001; Zelle-Rieser et al., 2002). Several reports have stressed the following roles of 5-lipoxygenase products in DC function: 1) deficient extracellular export of LTC4 is associated with a decreased migratory response of DCs (Robbiani et al., 2000), 2) cysteinyl-LT increase IL-10 production by myeloid DCs in a murine model of murine asthma (Machida et al., 2004), and 3) the dectin-2/cysteinyl-LT pathway is critical for the induction of Th2 immunity to major allergens (Barrett et al., 2011). Similar to the distinct responses observed in the different types of differentiated macrophages, AA metabolism in DCs shows distinct patterns in mature and immature DCs. Whereas the release of AA elicited by some ligands showed no difference between immature and tumor necrosis factor-a (TNFa)–mature cells, an enhanced expression of COX-2 was best observed in immature DCs (Valera et al., 2008), thus highlighting the distinct patterns of response associated with environmental cues. In the case of LPS, DCs express the LPS coreceptor CD14 at lower levels than macrophages (Segura et al., 2013) and this may explain the different intensity of the response. Regarding C-type lectin receptors, the engagement of dectin-1 has been the object of close attention since it is 191 192 Rodríguez et al. AA Metabolites Are Major Modulators of the Release of Cytokines from DCs IL-10, PGE2, and Downregulation of the Inflammatory Response. The induction of cytokines by fungal PAMPs has been the subject of detailed analysis. In the case of b-glucans, the pattern of cytokines includes a high production of TNFa, IL-6, IL-10, and IL-23, and a low secretion of IL-12 p70 (Rogers et al., 2005; Dillon et al., 2006; Gerosa et al., 2008). Since these cytokines are produced concomitantly with the release of eicosanoids, the question arises as to the role played by eicosanoids in the induction of those cytokines. The induction of the expression of TNFa and IL-6 can be explained on the basis of the activation of NF-kB, but the expression of IL-10 requires close attention due to its complex mechanism of regulation and its role in the downregulation of the inflammatory response. Most recent views have focused on signal transducer and activator of transcription 3 (Benkhart et al., 2000; Chang et al., 2007; Weichhart et al., 2008; Villagra et al., 2009) and CREB (Platzer et al., 1999; Hu et al., 2006; Alvarez et al., 2009a). The central role of CRE-dependent transcription on il10 regulation explains its strong PGE2 dependence, since one of the best effects of PGE2 is the activation of the system E prostanoid (EP) receptor/cAMP/PKA, which phosphorylates S133-CREB and creates a docking site for the coactivator CREB-binding protein and the initiation of il10 transactivation. In addition, PKA activity inhibits saltinduced kinases (SIKs), the function of which is to allow the cytoplasmic retention of CREB coactivators transducer of regulated CREB activity (TORC)/CREB-regulated transcriptional coactivator (CRTC) 2 and TORC/CRTC3 through their cytoplasmic docking to 14-3-3 proteins. In keeping with this mechanism, inhibition of SIK activity by the kinase inhibitor MRT67307 (N[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin4-yl]amino]propyl]cyclobutanecarboxamide) elevates IL-10 production by inducing the dephosphorylation of TORC/CRTC3, its dissociation from 14-3-3 proteins, and its translocation to the nucleus where it enhances the gene transcription program controlled by CREB. Proof of concept of the involvement of PGE2 in the PKA/SIK/CRTC3 pathway was recently provided (Clark et al., 2012; Mackenzie et al., 2013a). Taken together, these data show that PGE2 acting through EP receptors modulates two upstream elements of the EP/PKA/SIK/CRTCCREB pathway that reprograms macrophages to an antiinflammatory phenotype (Fig. 2). A corollary to these findings is that inhibition of SIK can be used as a molecular target to switch macrophage into an anti-inflammatory phenotype. In addition to the robust connection between PGE2 and IL-10 that explains a portion of the anti-inflammatory phenotypes in macrophages and DC, PGE2 can still repress TLR-induced cytokine induction in the absence of IL-10 (van der Pouw Kraan et al., 1995; Mackenzie et al., 2013a). Several studies have disclosed the distinct mechanisms involved in the modulation of cytokine production elicited by PGE2. Whereas the inhibitory effect of PGE2 on IL-6 induction was dependent on IL-10 as judged from its reversal by anti–IL-10 antibody, the production of IL-12 p70 was not influenced by this treatment (van der Pouw Kraan et al., 1995). The inhibitory effect on the induction of TNFa has been explained through PKA-anchoring protein 95, which positions the kinase in close proximity to its substrates, and interference with the phosphorylation of Ser536 in the C-terminal transactivation domain of the NF-kB family protein p105 (Wall et al., 2009). The inhibition of the inflammatory chemokines CCL3 and CCL4 has been explained through a signaling route involving EP/exchange protein activated by cAMP (EPAC)/phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3, which results in an increased binding of the CCAAT displacement protein to the regulatory regions of a variety of genes, where it behaves as a potent transcriptional repressor (Jing et al., 2004). Another way of cross-talk between IL-10 and PGE2 production has been disclosed by showing the inhibitory effect of IL-10 on ptgs2 mRNA expression. This was observed in different systems (Niiro et al., 1995; Berg et al., 2001; Shibata et al., 2005) and a mechanistic explanation was provided in a recent study by showing that IL-10 regulates ptgs2 mRNA via tristetraprolinedependent degradation (Mackenzie et al., 2013b). PGE2 and the IL-12 p70/IL-23 Balance. Some studies have shown the involvement of PGE2 in the production of Th1 responses (Nagamachi et al., 2007; Yao et al., 2009), but most work has stressed its ability to suppress the differentiation of functionally competent Th1-inducing DCs (Kali nski et al., 1997). The most accepted mechanism is that PGE2 weakens the Th1 response by inhibiting the production of the Th1polarizing cytokine IL-12 p70, because the expression of the IL-12 p40 chain is not accompanied by the parallel expression of the IL-12 p35 chain, which is necessary to form the bioactive IL-12 p70 heterodimer. This effect is so strong that the combination of PGE2 with other stimuli such as LPS and the CD40 ligand also results in failure to induce IL-12 p70 (Kali nski et al., 2001). Most recent studies have identified the DC resulting from PGE2 exposure as myeloid-derived suppressor cells (MDSCs) capable of suppressing cytotoxic T lymphocyte responses (Obermajer et al., 2011). IL-23 plays a central role in the expansion and maintenance of the Th17 phenotype, which agrees with the enhancing role of PGE2 on IL-23 production and Th17 polarization (Khayrullina et al., 2008; Boniface et al., 2009). This effect seems restricted to DCs and has not been observed in macrophages (Kalim and Groettrup, 2013). A recent study deciphered Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 has been reported recently by showing that PGE2 promotes the formation of a complex between the actin depolymerization factor cofilin-1 and phosphatase and tensin homolog deleted on chromosome 10 that decreases polymerization of F-actin and increases monomeric G-actin (Serezani et al., 2012). A recent study disclosed how the timing of eicosanoid production may be coupled to either pro- and anti-inflammatory responses during Candida infection (Suram et al., 2013). Granulocyte-colony stimulating factor (csf3 gene), a cytokine that regulates the production and function of polymorphonuclear leukocytes, was the gene showing the highest degree of induction in response to Candida and its expression was reduced in cPLA22/2 animals. The expression of il10 increased 78-fold in cPLA2a1/1 mice compared with only 7-fold in the cPLA22/2 mice. Conversely, TNFa expression was increased in cPLA2a2/2 mice treated with Candida compared with wild-type animals. These findings are in keeping with the reported role of PGE2 in the induction of the Th17 response and the central role of IL-17 in host defense in candidiasis (Conti et al., 2009; Ferwerda et al., 2009; Puel et al., 2011), and also show that Candida stimulates an autocrine loop in macrophages involving cPLA2a, PG, and cAMP that globally effects expression of genes involved in host defense and the control of inflammation. Eicosanoids in Innate Immunity 193 the PGE2-triggered signaling pathway from the most proximal EP receptors to transcription factor activation and binding to the promoter of il23a (i.e., the gene encoding the IL-23 p19 chain that dimerizes with IL-12 p40 to form the IL-23 heterodimer) (Kocieda et al., 2012). This mechanism is consistent with the aforementioned general route including EP receptors/cAMP/PKA/P-CREB, but a portion of the effect depends on the activation of EPAC by cAMP and is related to an effect on C/EBPb transcriptional activity rather than on CREB-mediated trans-activation. The response is mediated primarily through EP4 and to a lesser extent via EP2. The effect of PGE2 was only observed when it was used in combination with LPS, which is consistent with the need for cooperation with other transcription factors activated by LPS, such as NF-kB and/or C/EBPb. Further analysis showed that two putative CREB binding sites in the il23a promoter were involved in transcriptional regulation and that the CREB distal site is an important regulator of EP4-induced il23a transcription (Fig. 3). A thorough scrutiny of the distinct role of the different EP receptors in human DC was recently reported (Poloso et al., 2013). By using selective EP receptor antagonists, it was observed that PGE2 controls IL-23 release in a dose-dependent manner by differential use of EP2 and EP4. Low concentrations of PGE2 trans-activate il23a via EP4, whereas concentrations above 50 nM suppress IL-23 by an EP2-dependent mechanism. The Contribution of Animal Models to Decipher the Function of PGE2 in the Innate Immune Response The Different EP Receptor Subtypes. The apparently opposing biologic effects of PGE2 can be explained by its distinct actions on many cell types. On the one hand, PGE2 promotes local vasodilatation, inflammatory edema, and local attraction and activation of leukocytes. On the other hand, its prominent effects on the induction of suppressive IL-10 and blunting of IL-12 p70 production account for its immunomodulatory properties. These actions explain that the most outstanding effect of PGE2 in in vivo models is to keep excessive inflammatory responses at bay. A risk derived from this action is that it may contribute to the immune suppression Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 Fig. 2. The mechanism whereby PGE2 promotes the transcription of il10 in LPS- and zymosan-stimulated macrophages and DCs. Binding of PGE2 to the EP2 and EP4 receptors triggers the production of cAMP and the activation of PKA. PKA induces the phosphorylation of S133-CREB and the phosphorylation/inactivation of SIKs. P-S133-CREB binds to the CRE site in the il10 promoter, whereas dephosphorylation of TORC/CRTC2 and TORC/ CRTC3 by the serine-threonine phosphatase calcineurin releases the cytoplasmic retention of these coactivators by binding to 14-3-3 proteins and allows their nuclear translocation and interaction with the complex P-CREB/CREB-binding protein to initiate the transcriptional response. The scheme has been elaborated from results reported by Alvarez et al. (2009a), Clark et al. (2012), and Mackenzie et al. (2013a). The indication of acetylated lysines is explained by the relevance of these post-translational modifications related to the lysine acetyltransferase activity of CREB-binding protein. 194 Rodríguez et al. associated with chronic inflammation and cancer. Notably, PGE2 on its own induces high levels of COX-2 in differentiating MDSCs and initiates a positive feedback loop that stabilizes the suppressive functions of MDSCs (Obermajer et al., 2011). The distinct effects of PGE2 are best explained not only by the existence of four different EP receptors, but also by the diversity resulting from multiple variants of EP3 due to alternative splicing of its C-terminal tail. Although EP receptors are G-protein coupled, they are structurally and functionally distinct, have limited amino acid identity, and show variable levels of expression among the different tissues. EP3 and EP4 represent high-affinity receptors, whereas EP1 and EP2 require significantly higher concentrations of PGE2 for effective signaling (see Sugimoto and Narumiya, 2007, for a review). EP2 and EP4 signaling mainly depends on the cAMP/PKA/CREB pathway (Gas-coupling), and they mediate the most relevant anti-inflammatory and suppressive activity of PGE2. However, a detailed scrutiny of the function of EP2 and EP4 disclosed that EP4 ligation induces a weaker stimulation of intracellular cAMP compared with the ligation of EP2 expressed at similar levels. Unlike EP2, EP4 can also be coupled to b-arrestin and b-catenin (Yokoyama et al., 2013). This explains the formation of an EP4/b-arrestin 1/cSrc signaling complex that plays an important role in cancer cell migration (Kim et al., 2010) and in DC function (De Keijzer et al., 2013). EP1 is coupled to a yet unknown G protein, but binding of PGE2 to this receptor type leads to a transient increase in intracellular Ca21 concentration and to activation of PLCb, presumably by coupling to a Gaq protein. The G-protein coupling of EP3 is more promiscuous in view of the different C-terminal splice variants that signal via Gaq and Gai proteins and induce an increase of inositoltrisphosphate and Ca21 (Gaq-coupling) or a decrease of cAMP (Gai-coupling). This array of differences in sensitivity, susceptibility to desensitization, and ability to activate different signaling pathways among the different EP receptors allows Downloaded from molpharm.aspetjournals.org at ASPET Journals on August 3, 2017 Fig. 3. Cooperation of PGE2 and TLR4 signaling in the induction of il23a transcriptional activation in murine bone marrow–derived DCs. PGE2 activates transcription factors that cooperate with NF-kB proteins. Part of the signals are conveyed via cAMP and PKA and allow the activation of CREB. In addition, EPAC contributes to the activation of C/EBPb that binds to a site in the proximal promoter. P, phosphate. This diagram was constructed from data by Kocieda et al. (2012). Eicosanoids in Innate Immunity Concluding Remarks Eicosanoids are generated as a result of the signaling cascades triggered by the binding of PAMPs to their cognate PRRs. This makes the innate immune response one of the most relevant settings in which eicosanoids play a pathophysiological role. Signaling cascades based on phosphorylation and Ca21-driven translocation of cPLA2a are involved in the rapid generation of eicosanoids, whereas induction of the expression of COX-2 by activation of transcription factors such as NF-kB, CREB, and C/EBPb explains the delayed and high-rate production of PGE2 and PGD2 associated with processing the AA available as a result of the basal acylation/ deacylation cycle. The distinct ligand-binding properties of the PRR, the different signaling mechanisms associated, and the cooperation of receptors in the binding of microbialderived particles explain the different patterns of responses that can be observed. Another layer of complexity is provided by the role of opsonic proteins. In this connection, complement coating of PAMPs seems essential for the activation of polymorphonuclears and monocytes by particles mimicking the fungal cell wall, whereas monocyte-derived DCs are a cell type specially endowed to respond to fungal patterns in the absence of opsonins. The analysis of PGE 2 effects has disclosed its capacity for the following: 1) to inhibit phagocytosis and to enhance mortality in models of fungal and polymicrobial infection, 2) to stabilize the suppressive functions of MDSCs, 3) to promote an anti-inflammatory phenotype in macrophages associated with a high production of IL-10, and 4) to inhibit IL-12 p70 and to enhance the production of IL-23. The application of mechanistic data on the role of kinases such as SYK and SIK in modulating PGE2 production and the selective modulation of EP receptor signaling can be valuable clues to develop useful pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases. 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Studies in animal models of infection have shown that PGE2 differentially affects cytokine production depending on the developmental state of the cell. In contrast to in vitro studies in which PGE2 was found to enhance the Th17 immune response (Khayrullina et al., 2008), PGE2 has been reported to suppress antifungal immunity by inhibiting IFN regulatory factor 4 function and IL-17 expression in T cells in a mouse model of Cryptococcus neoformans infection (Valdez et al., 2012). Likewise, EP2 and EP4 activation suppresses pulmonary host defenses through increases in cAMP (Aronoff et al., 2004; Ballinger et al., 2006; Sadikot et al., 2007). EP3 is also involved in the suppression of host defenses, since EP32/2 are protected from pneumococcal mortality (Aronoff et al., 2009). 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