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PHARMACOLOGICAL REVIEWS
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/pr.114.009001
Pharmacol Rev 67:259–279, April 2015
ASSOCIATE EDITOR: QIANG MA
The Aryl Hydrocarbon Receptor in Barrier Organ
Physiology, Immunology, and Toxicology
Charlotte Esser and Agneta Rannug
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany (C.E.); and Institute of
Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (A.R.)
This research was supported by the German Research Foundation [Grants ES103/6 and ES103/5 (to C.E.)] and the Swedish Research
Council Formas [Grant 216-2011-1364 (to A.R.)].
Address correspondence to: Dr. Charlotte Esser, Leibniz Research Institute for Environmental Medicine, Auf´m Hennekamp 50, 40225
Düsseldorf, Germany. E-mail: [email protected]
dx.doi.org/10.1124/pr.114.009001.
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Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
II. Aryl Hydrocarbon Receptor Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
A. The Canonical Signaling Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
B. Noncanonical Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
C. Aryl Hydrocarbon Receptor–Dependent Transcription. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
D. The Realm of Aryl Hydrocarbon Receptor Ligands: Agonists and Antagonists. . . . . . . . . . . . . 263
III. Role of the Aryl Hydrocarbon Receptor in the Barrier Immune System. . . . . . . . . . . . . . . . . . . . . . . 264
A. Differential and Variable Aryl Hydrocarbon Receptor Expression Levels in Cells and
Tissues, Including the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
B. Aryl Hydrocarbon Receptor in the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
1. The Dermis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
2. The Epidermis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
3. Aryl Hydrocarbon Receptor–Mediated Skin Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
4. Aryl Hydrocarbon Receptor in Two Skin-Specific Innate Immune Cells. . . . . . . . . . . . . . . . 266
5. High-Affinity Aryl Hydrocarbon Receptor Ligands in the Skin. . . . . . . . . . . . . . . . . . . . . . . . . 267
C. Aryl Hydrocarbon Receptor in the Gut and Consequences for Gut Health and Microbiome . . 267
1. The Gut-Associated Immune System: A Paradigm of Immune Activation and
Suppression.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
2. Aryl Hydrocarbon Receptor in Innate Immune Cells of the Gut.. . . . . . . . . . . . . . . . . . . . . . . 267
3. Systemic Effects of Oral Aryl Hydrocarbon Receptor Ligand Exposure. . . . . . . . . . . . . . . . . 268
4. Role of Dietary Ligands in Development of the Innate Gut Immunity. . . . . . . . . . . . . . . . . 268
D. Aryl Hydrocarbon Receptor in the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
1. Lung Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
2. Respiratory Viral Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
3. Lung Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
IV. The Aryl Hydrocarbon Receptor in Toxicology and Physiology of the Human Skin, Lung,
and Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
V. The Aryl Hydrocarbon Receptor: Promiscuous Sensing of Chemicals or Metabolic
Control of the Endogenous High-Affinity Ligand FICZ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
VI. Therapeutic Potential of Aryl Hydrocarbon Receptor Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
VII. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
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Esser and Rannug
Abstract——The aryl hydrocarbon receptor (AhR) is
an evolutionarily old transcription factor belonging to
the Per-ARNT-Sim–basic helix-loop-helix protein family.
AhR translocates into the nucleus upon binding of
various small molecules into the pocket of its singleligand binding domain. AhR binding to both xenobiotic
and endogenous ligands results in highly cell-specific
transcriptome changes and in changes in cellular
functions. We discuss here the role of AhR for immune
cells of the barrier organs: skin, gut, and lung. Both
adaptive and innate immune cells require AhR signaling
at critical checkpoints. We also discuss the current two
prevailing views—namely, 1) AhR as a promiscuous
sensor for small chemicals and 2) a role for AhR as
a balancing factor for cell differentiation and function,
which is controlled by levels of endogenous high-affinity
ligands. AhR signaling is considered a promising drug and
preventive target, particularly for cancer, inflammatory,
and autoimmune diseases. Therefore, understanding its
biology is of great importance.
I. Introduction
low-density lipoproteins, hydrogen peroxide, ozone, or
metals (references in Wincent et al., 2012). Much of this
is not understood because the AhR has not yet been
crystallized, although it was cloned more than 2 decades
ago (Burbach et al., 1992).
Research on the AhR has undergone a major paradigm
shift in recent years. It has long focused on induction of
genes coding for metabolizing enzymes, the so-called
AhR-battery genes (Nebert et al., 1991; Köhle and Bock,
2007). In particular, cytochrome P450 was of interest
because of the toxicity associated with its activity in
adverse drug–drug interactions and generation of carcinogenic metabolites from polycyclic aromatic hydrocarbons (PAHs). Especially in the field of toxicology and
pharmacology, the AhR is viewed as a protein that has
developed during evolution to mediate metabolization of
environmental small molecules. This view of the AhR as
a promiscuous cytosolic sensor of small molecules that is
primarily involved in biotransformation and detoxification is rapidly changing. As regarded today, the AhR
plays an important role in cell development, differentiation, and function. Recent evidence from studies with
full and conditional AhR-deficient animal models implies
important endogenous roles for the AhR. These include
control in perinatal growth, fertility, hepatic and vascular
development, peripheral and intestinal immunity and
hematopoiesis, as well as in stem cell expansion and
cancer. The specific ligands that are drivers of activation
in a given situation are not fully clear.
It is recognized that xenobiotic small chemicals can
aberrantly activate AhR because of their structural
likeness to physiologic ligands. By this process, chemicals may increase the metabolic turnover of physiologic
ligands and thereby decrease the half-life of the latter.
As a result, uncontrolled or persistent activation of the
AhR by exogenous small molecules may disturb the tightly
controlled and transient AhR-regulated cell functions.
This could be the underlying cause of the toxicity of
The environment offers both vital benefits, such as
food and sunlight, and deadly risks, such as infectious
pathogens and toxins. The role of epithelial barrier
organs such as skin, gut, lung, and other mucosal tissues
that interact with the environment is critical for survival.
Furthermore, these barriers are involved in uptake and
absorption of nutrients as well as protection of body
integrity against chemical, biologic, and physical stress,
and more. The aryl hydrocarbon receptor (AhR) is a latent
cytoplasmic transcription factor that can be activated by
certain low molecular weight chemicals. The AhR is
highly expressed in many barrier organs and in the liver,
and its expression pattern conceivably suggests a role
as a sensor of chemicals. Many AhR-activating factors,
which cause transcriptional activation, have been identified (Denison and Nagy, 2003). They range from environmental pollutants, such as polyhalogenated aromatic
hydrocarbons (PHAHs), to endogenous amino acid derivatives, dietary chemicals such as indoles or glucosinolates,
and finally natural substances found in yeasts and
bacteria or even marine sponges. As demonstrated by
in vitro studies and gene expression profiles, the transcriptional changes by the activated AhR are ligand
specific and are highly cell specific. For a given cell type,
they may even depend on the tissue milieu, such as an
ongoing immune response (Sun et al., 2004; Frericks
et al., 2007; Beischlag et al., 2008; Tappenden et al.,
2013). There appears to be only one ligand binding
pocket in the AhR [in the Per-ARNT-Sim-B domain],
and the binding affinity of the best characterized highaffinity ligand, TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin), depends on only a few amino acids in the binding
pocket of the AhR, as demonstrated by modeling and
mutation studies (Whelan et al., 2010; DeGroot et al.,
2012; Wu et al., 2013). The AhR can also be activated
by numerous stress factors and substances that may not
fit into the binding pocket, such as hyperoxia, oxidized
ABBREVIATIONS: AD, atopic dermatitis; AhR, aryl hydrocarbon receptor; AhRE, aryl hydrocarbon receptor responsive element; ARNT,
aryl hydrocarbon receptor nuclear translocator; COPD, chronic obstructive pulmonary disease; DC, dendritic cell; DETC, dendritic epidermal
T cell; DSS, dextran sodium sulfate; FICZ, 6-formylindolo[3,2-b]carbazole; GNF351, N-(2-(3H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methyl-3pyridyl)-7H-purin-6-amine; I3C, indole-3-carbinol; ICZ, indolo[3,2-b]carbazole; IEC, intestinal epithelial cell; IEL, intraepithelial lymphocyte;
IL, interleukin; ILC, innate lymphoid cell; ITE, 2-(19H-indole-39-carbonyl)-thiazole-4-carboxylic acid methyl ester; LBD, ligand binding
domain; LC, Langerhans cell; MG132, carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; NK, natural killer; PAH, polycyclic aromatic hydrocarbon;
PHAH, polyhalogenated aromatic hydrocarbon; SAhRM, selective aryl hydrocarbon receptor modulator; TCDD, 2,3,7,8-tetrachlorodibenzo-pdioxin (“dioxin”); TCR, T-cell receptor; Th, helper T cell; Treg, regulatory T cell; VAF347, (4-(3-chloro-phenyl)-pyrimidin-2-yl)-(4-trifluoromethylphenyl)-amine.
Aryl Hydrocarbon Receptor in Immunology and Toxicology
ligands such as dioxins and biphenyls. The link between
environment and immunity is particularly intriguing
(Kimura et al., 2008; Quintana et al., 2008; Veldhoen
et al., 2008; Esser et al., 2009) because it was known
that allergies, autoimmune diseases, or immunotoxicity
could be caused by chemicals and drugs, although the
underlying molecular mechanism and signaling pathways were often unclear. Notably, xenobiotic ligands
of the AhR, especially TCDD, are known to adversely
affect immune cells, which could simply reflect a disruption of endogenous, AhR-driven homeostasis.
In any case, the strong flexibility of AhR activation
by chemicals makes it an attractive pharmacological
target, as evident from experiments on stem cell proliferation and inhibition of cancer cells (Safe and McDougal,
2002; Lawrence et al., 2008; Singh et al., 2009; Boitano
et al., 2010).
Barrier organs—skin, gut, lung, and eyes, and oral
and genital mucosal tissues—specialize in discerning
harm from good and can trigger or orchestrate adaptive
physiologic responses. Chemicals from the environment,
including small molecules from symbiotic and pathogenic microbes, are first encountered at the barriers.
With respect to immunologic functions, a network of
tissue-specific immune cells is on watch constantly and
attracts immune cells from the blood stream or lymph
when needed. An important feature of barrier immunity
is the distinction between harmful pathogens and
harmless microorganisms and protein antigens (e.g.,
from food), against which active tolerance must be
maintained. Moreover, we begin to understand that the
(symbiotic) microflora and their metabolic products, in
turn, shape immunity and tolerance (Schulz et al., 2011;
Mavrommatis et al., 2013). Recently, it was discovered
that AhR can be involved in disease tolerance and can
also be a sensor of bacterial danger by sensing bacterial
pigmented virulence factors (Bessede et al., 2014; MouraAlves et al., 2014).
High levels of AhR expression were detected in hematopoietic stem cells, in cells of the innate immune system,
and also in T-cell subsets and B cells. Exposure to AhR
ligands changes the function and fate of these cells.
Research using various ligands and/or genetically
engineered mouse models has demonstrated that AhR
is involved in both correct development of naïve cells
and in effector functions during an immune response.
Here, we review the functions of ligand-activated AhR
signaling in the specialized context of barrier organs,
especially regarding the immunologic barrier against
the environment.
II. Aryl Hydrocarbon Receptor Signaling
A. The Canonical Signaling Pathway
The AhR is a basic helix-loop-helix, Per-ARNT-Sim–
containing ligand-dependent transcription factor. It has
close structural homology to proteins found in pathways
261
that regulate hypoxia and circadian rhythms (McIntosh
et al., 2010). In the absence of ligand, AhR resides in the
cytoplasm as a component of a chaperone complex that
includes a dimer of Hsp90, together with the cochaperones p23, and AIP, the AhR-interacting protein also
known as ARA9, and XAP2 (reviewed by Denison et al.,
2011). As depicted in Fig. 1, the translocation of AhR
into the nucleus is initiated upon ligand binding and
phosphorylation of two protein kinase C sites adjacent
to the nuclear localization sequences (Ikuta et al., 2004;
McIntosh et al., 2010). AhR dissociates from its chaperone
complex and forms a heterodimer with ARNT in the
nucleus. The AhR–ARNT dimer then binds to upstream
regulatory regions of its target genes (e.g., the cytochrome
P450 family 1 gene, CYP1A1). The target genes contain
canonical aryl hydrocarbon receptor responsive elements
(AhREs, also known as dioxin responsive element or
xenobiotic responsive element) having the core sequence
59-TNGCGTG-39. The complex with DNA then recruits
coactivators, which alter the chromatin structure into a
more accessible configuration through histone acetyltransferase and histone methyltransferase activities. Other
factors are recruited, including the kinases IKKa, MSK1,
and MSK2, the coactivators SP1, NCOA1, NCOA3, NCOA4,
and p300, the BRCA1 tumor suppressor protein, and the
general transcription factor IIB. The latter is required for
transcriptional initiation by RNA polymerase II (Beischlag
et al., 2008; Sartor et al., 2009; Taylor et al., 2009; McIntosh
et al., 2010; Kurita et al., 2014).
B. Noncanonical Signaling
Cross-talk between the AhR and other signaling pathways can lead to noncanonical mechanisms of actions of
the AhR and AhR ligands. Several types of cross-talk
have been described as a result of molecular interaction
between activated AhR and other proteins, by competition
for transcriptional coactivators/repressors, by coactivatorlike interactions, or by direct binding (reviewed by
Denison et al., 2011). In the nucleus, AhR was found
to associate with the hypophosphorylated form of pRB
resulting in growth arrest at the G1/S phase of the cell
cycle (Levine-Fridman et al., 2004). AhR binds to the
transcription factor c-Maf, which is important for regulatory type 1 T-cell differentiation (Apetoh et al., 2010). The
AhR also binds STAT1, resulting in nuclear factor-kB
promoter activity (Kimura et al., 2009). In addition,
interactions of AhR have been described for the estrogen
receptor, b-catenin, Nrf2, RelA, and RelB (Kim et al.,
2000; Vogel et al., 2004, 2007; Miao et al., 2005; Braeuning
et al., 2011; Procházková et al., 2011).
Ligand binding to AhR also gives rise to alternative
actions (nongenomic) such as a rapid increase in intracellular Ca 2+ concentration leading to downstream
proinflammatory responses mediated by c-src, COX2, and
CCL1 (Nebert et al., 1993; N’Diaye et al., 2006; Fritsche
et al., 2007; Matsumura, 2009; Zhou et al., 2013). Many of
the details and the physiologic importance are still unclear.
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Esser and Rannug
Fig. 1. Scheme of AhR signaling. Events leading from AhR ligand binding to transcription. AhR resides in cytosol in a complex of chaperones and other
proteins (I). Upon ligand binding (I), AhR changes conformation. As a consequence, the complexing proteins are shed (II). c-src can contribute to
cytoplasmic signaling on its own (IIa). Second, the nuclear translocation site in the bHLH region is exposed. Release of AIP permits docking of importin,
which mediates nuclear import. AhR dimerizes with ARNT or other partners from other signaling pathways (IIIa and IIIb). Finally, the AhR:
PARTNER complex binds to DNA at specific elements (either AhREs, NFkB elements, or others) and recruits transcription cofactors (IV). Targeted
genes are transcribed, leading to cell-specific transcriptome changes. Finally, AhR is exported and degraded (V). AhR signaling flexibility is shaped on
different levels, especially by formation of complexes with other proteins (cross-talk). AIP, AhR-interacting protein; ER, estrogen receptor; iNOS,
inducible nitric oxide synthase; MMP, matrix metalloproteinase; NFkB, nuclear factor-kB; PGHS, prostaglandin synthase; RB, retinoblastoma protein;
TNF-a, tumor necrosis factor a; XME, xenobiotic metabolizing enzymes.
AhR activity can be modulated by the activity of
other signaling pathways. A relevant example is the
Wnt/b-catenin pathway. This pathway is important for
the maintenance of cell pools through self-renewal of
hematopoietic stem cells, intestinal and gastric stem
cells, hair and melanocyte stem cells, as well as neural
and liver progenitor cells (Clevers, 2006; Tan et al.,
2006; Van Camp et al., 2014). It is also essential for
development of early T precursor cells, both for the
events needed to generate mature naïve T cells and
for the peripheral differentiation of naïve T cells into
inflammatory and regulatory T-cell subsets (Clevers,
2006; Ma et al., 2012; Xue and Zhao, 2012).
Of great scientific interest is the role that the AhR
seems to play in progenitor cell expansion and differentiation in which the Wnt/b-catenin pathway is active
(Laiosa et al., 2003; Singh et al., 2009; Boitano et al.,
2010; Latchney et al., 2011; Procházková et al., 2011).
Furthermore, a role for AhR in tissue regeneration has
been described in models of liver, fin, and cardiac tissue
regeneration (Mathew et al., 2006; Mitchell et al., 2006;
Hofsteen et al., 2013).
There is an increased understanding of different types
of cross-talk between the AhR and Wnt/b-catenin pathways. The Wnt pathway leads to nuclear localization of
b-catenin, which can then interact with the DNA-binding
TCF/LEF proteins to activate transcription of Wnt/b-catenin
target genes. Signaling through b-catenin has been
found to work cooperatively with AhR signaling in vitro
and in vivo. Both basal and TCDD-stimulated CYP1A1
expression are influenced by the presence of b-catenin
(Braeuning et al., 2011). Wnt/b-catenin signaling is involved in both stem cell and cancer cell maintenance and
growth. It is tightly controlled by the so-called destruction
complex, and either too much or too little b-catenin has
negative consequences (Duncan et al., 2005). Notably, the
AhR acts as an adaptor protein in the CUL4B:AhR
cullin 4B ubiquitin ligase complex (Ohtake et al., 2007). By
activating the ubiquitin-proteasome system, the ligandactivated AhR targets several proteins for degradation
including the AhR itself, b-catenin, and some sex steroid
receptors (Kawajiri et al., 2009; Ohtake et al., 2011).
Consistently, rapidly renewing tissues and cells such
as skin, gut, and blood cells are all targets of TCDD
Aryl Hydrocarbon Receptor in Immunology and Toxicology
toxicity (as detailed below in section III) and are affected
in AhR knockout and AhR-overexpressing mice. Increased knowledge on the interaction of AhR with
the Wnt/b-catenin pathway is important to increase
our understanding of the role of the AhR in toxicology
as well as for the development of new therapeutic
applications.
C. Aryl Hydrocarbon Receptor–Dependent
Transcription
The AhR transcriptional induction profile has been
extensively studied. Binding to the AhRE consensus
sequences initiates transcription of a great number of
genes. Originally, Daniel Nebert described a battery of
six AhR-dependent genes coding for xenobiotic metabolizing enzymes (Nebert, 1989). Today, the number of
genes that respond to AhR activation by TCDD or other
exogenous compounds is proposed to be on the order of
600 (Sartor et al., 2009; Dere et al., 2011). Among the
most highly upregulated genes is the AhR repressor,
which shares structural homology with AhR and ARNT
(Mimura et al., 1999), and TiPARP (MacPherson et al.,
2014). Both proteins repress AhR. In addition, the genes
coding for the CYP1A and CYP1A2 enzymes, which
contain multiple functional AhREs in their shared
enhancer region, is highly inducible. CYP1 enzymes
can metabolically degrade small endogenous high-affinity
ligands and can thereby control constitutive AhRdependent transcription.
Transcriptomics and functional analyses, performed
in the presence or absence of exogenous ligands, have
revealed AhR target gene networks that control a broad
spectrum of cellular functions. This concerns inter alia
the immune system and nervous system development,
embryonic development, eye development, tube morphogenesis, angiogenesis, and patterning of blood vessels. In the comprehensive genome-wide analysis of the
AhR target gene profile performed by Alvaro Puga and
coworkers, an unexpected large number of gene promoter regions exhibited significant AhR binding in
unstimulated cells (Sartor et al., 2009). They reported
that their gene ontology analyses gave unanticipated
results that suggested a prominent role of the AhR in
regulatory interactions with the Wnt/b pathway as also
discussed above (Sartor et al., 2009).
D. The Realm of Aryl Hydrocarbon Receptor Ligands:
Agonists and Antagonists
The enigma of an endogenous or physiologic ligand
has intrigued the AhR research community for a long
time. A three-dimensional structure of the AhR or at
least its ligand binding domain (LBD) is still lacking.
However, the approximate dimensions of the ligand
binding pocket and several critical amino acid residues
in the binding pocket are known. This knowledge has
enabled docking studies of proposed AhR ligands (Goryo
et al., 2007; Soshilov and Denison, 2014).
263
By now, there are only a few types of molecules that
have been demonstrated to fit exceptionally well into
the LBD and to activate the receptor at concentrations
in the picomolar or nanomolar range. Among the highaffinity exogenous substances are several planar and
lipophilic PHAHs of the dioxin, dibenzofuran, biphenyl,
and azoxybenzene types sharing structural properties
with the highly toxic TCDD (Nguyen and Bradfield,
2008). In addition, some planar, lipophilic nonhalogenated
PAHs bind to the AhR with high affinity. These include
benzo[a]anthracene, benzo[a]pyrene, benzo[b]fluoranthene,
benzo[k]fluoranthene, chrysene, dibenzo[a,h]anthracene,
indeno[1,2,3,c,d]pyrene, 3-methylcholanthrene, and
b-naphthoflavone (Till et al., 1999; Nguyen and Bradfield,
2008). The bacterial pigment 1-hydroxyphenazine and
three pharmacological agents, StemRegenin 1 and
GNF351 [N-(2-(3H-indol-3-yl)ethyl)-9-isopropyl-2-(5methyl-3-pyridyl)-7H-purin-6-amine] (two potent AhR
antagonists), as well as VAF347 [(4-(3-chloro-phenyl)pyrimidin-2-yl)-(4-trifluoromethyl-phenyl)-amine], have
also been observed to be high-affinity ligands (Lawrence
et al., 2008; Boitano et al., 2010; Smith et al., 2011; MouraAlves et al., 2014). Many of these exogenous compounds
probably bear structural similarities to physiologic
ligand(s).
The search for bona fide endogenous ligands that
induce AhR signaling under physiologic conditions has
only produced a small number of candidates. These
include one metabolite of arachidonic acid, lipoxin 4A
(Schaldach et al., 1999), and the four indoles, FICZ
(6-formylindolo[3,2-b]carbazole) (Rannug et al., 1987),
indirubin (Adachi et al., 2001), ITE [2-(19H-indole-39carbonyl)-thiazole-4-carboxylic acid methyl ester] (Song
et al., 2002), and ICZ (indolo[3,2-b]carbazole) (Bjeldanes
et al., 1991). In addition, the indolic AhR proligands
such as indole-3-carbinol (I3C) and tryptamine may be
converted in the body to the high-affinity ligands ICZ or
FICZ (Bjeldanes et al., 1991; Vikström Bergander et al.,
2012). L-Kynurenine, kynurenic acid, and cinnabarinic
acid are other endogenous molecules that are formed via
catalytic breakdown of tryptophan. They can activate
AhR signaling at levels that are physiologically or
pathophysiologically relevant (DiNatale et al., 2010;
Opitz et al., 2011; DeGroot and Denison, 2014; Lowe
et al., 2014).
Table 1 lists different types of small molecules and
other factors that have been identified as AhR activators
and ligands. In Fig. 2, we display three-dimensional
models of high- and low-affinity ligands and an antagonist.
Often identification of a chemical as a ligand is accomplished by assays using AhR-dependent transcription and
electrophoretic band shifts as proxy readouts. In a note of
caution, such assays may not always reflect AhR ligand
binding in the LBD. In particular, oxidative stress,
inflammatory mediators, and many physical stress factors
(exposures that strongly suppress CYP1A1 transcription if added together with inducers such as TCDD or
264
Esser and Rannug
b-naphthoflavone) have repeatedly been demonstrated
to activate AhR-dependent transcription by themselves
without direct binding (Gonder et al., 1985; Crawford
et al., 1997; Tanaka et al., 2005; Becker et al., 2006;
McMillan and Bradfield, 2007; Afaq et al., 2009; AnwarMohamed et al., 2009; Wincent et al., 2012). Electrophoretic band shifts exhibiting formation of AhR-AhRE
complexes have been detected with nuclear extracts from
cells cultured in the absence of added ligands and in cells
subjected to various stressful conditions (e.g., hyperoxia,
metals, low temperature, immune cell activators, the
proteolysis inhibitor MG132 (carbobenzoxy-L-leucyl-Lleucyl-L-leucinal), or detached growth (Sadek and AllenHoffmann, 1994; Crawford et al., 1997; Monk et al., 2001;
Santiago-Josefat et al., 2001; Tamaki et al., 2005; Elbekai
and El-Kadi, 2007). Some authors have suggested the
possibility that AhR-DNA interactions might result from
disruption of the molecular interaction between the
receptor and the chaperone HSP90, through transient
increases in AhR or ARNT expression, or through
increased production of endogenous ligands (Pongratz
et al., 1992; Sadek and Allen-Hoffmann, 1994; Monk
et al., 2001; Santiago-Josefat et al., 2001; Kann et al.,
2005; Tamaki et al., 2005; Elbekai and El-Kadi, 2007).
There are two other mechanisms that are primarily
discussed with regard to AhR activation by factors that
do not bind at all or that do not fit well into the AhR
LBD (discussed further in section V). The first one claims
that the AhR is promiscuous and AhR signaling can be
activated by structurally very diverse chemicals even at
low affinity (Denison et al., 2011; Soshilov and Denison,
2014). The second one claims that seemingly genuine
AhR activators inhibit the transcription and/or activity of
CYP1A1 and thereby inhibit the metabolic degradation
of the endogenous ligand FICZ (Wincent et al., 2012).
Soshilov and Denison (2014) have challenged this latter
indirect mechanism. They employed site-directed mutagenesis of the LBD of AhR and describe one particular
mutant, I319K, which was activated only by FICZ in
a luciferase reporter system. They argue that indirect
activation via FICZ, by some other AhR activators tested,
could not be involved because these other substances did
not activate the I319K mutant. However, FICZ-mediated
activation of the I319K mutant was only demonstrated at
a relatively high concentration of FICZ (0.1 mM) and not
at the picomolar concentrations present in cell culture
media under normal cell culture conditions (Oberg et al.,
2005; Wincent et al., 2009). Therefore, indirect activation
via FICZ cannot be ruled out on the basis of observations
with this mutant.
III. Role of the Aryl Hydrocarbon Receptor in the
Barrier Immune System
A. Differential and Variable Aryl Hydrocarbon
Receptor Expression Levels in Cells and Tissues,
Including the Immune System
AhR expression differs significantly between tissues.
It is not or only very weakly expressed in muscle
tissues, testes, kidney, and brain (both in human and
in mouse) (Dolwick et al., 1993; Li et al., 1994; Frericks
et al., 2007; Veldhoen et al., 2008). Of course, it is possible
that some subsets of cells in these tissues express AhR at
high levels, which is not detected when analyzing the
whole tissue. Unfortunately, a careful analysis of distinct
cell subsets is not available for many tissues. However,
constitutive AhR expression is conspicuously high in liver
and in the barrier tissues such as skin, lung, gut, and
mucosal epithelia as well as in the placenta. These tissues
contain immune cells, many of which express AhR at high
levels. With respect to the adaptive immune system, AhR
is low in naïve T cells, helper T cells Th1 and Th2, and
regulatory T cells but is high in Th17 cells and both the
interleukin (IL)-17/IL-22–producing and IL-17/IL-22–
nonproducing subsets of peripheral gd T cells (Veldhoen
et al., 2008; Martin et al., 2009). AhR is present at low
levels in naïve B cells from the spleen and is induced
upon polyclonal activation (Marcus et al., 1998). As
reviewed elsewhere, T and B cells are targets of AhRactivating factors. For instance, Th17 cells need AhR
activation for IL-22 secretion, and the immunoglobulin
locus can be suppressed by TCDD in an AhR-dependent
fashion (Esser et al., 2009; Sulentic and Kaminski, 2011;
Quintana and Sherr, 2013). Natural killer (NK) cells
express AhR at moderate levels, and AhR activation
stimulates antitumor activity as well as resistance to
infections (Wagage et al., 2014). However, the examples
of naïve B cells or NK cells suggest caution on simplifying
projections such as, “AhR is only relevant when expressed
in higher amounts.” AhR can be induced by immunologic
TABLE 1
Different types of AhR activators
The term AhR activator (rather than ligand) is used here to indicate that factors that do not bind to the LBD and trigger the canonical signaling pathway can also activate
AhR, for instance, via changing the cellular levels of FICZ or modulating chaperones. For a more exhaustive list and references, see Wincent et al. (2012).
AhR Activators with
No or Very Low Binding Potential
Low-Affinity Ligands (Binding Affinity in
the Micromolar to Millimolar Range)
Inflammatory mediators, glutathione depletion, Drugs, biochemical model compounds,
combustion products, food mutagens, hair
hydrogen peroxide, hyperoxia, metals and
dyes, hemes, humic acids, indoles, flame
metalloids, neurotoxins, organic solvents,
retardants, food additives, phytochemicals,
oxidized lipids, ozone, quartz, shear stress
plastic materials and additives, specific
and miscellaneous materials, etc.
antagonists and blockers, etc.
High-Affinity Ligands (Binding Affinity in
the Picomolar to Nanomolar Range)
FICZ, GNF351, ICZ, indirubin, ITE, lipoxin 4A,
StemRegenin 1, TCDD and some other
PHAHs, some PAHs, VAF347, and
1-hydroxyphenazine
Aryl Hydrocarbon Receptor in Immunology and Toxicology
Fig. 2. Space-filling models of some AhR-interacting substances. TCDD,
FICZ, and ICZ are all planar molecules that occupy approximately the
same space in the AhR LBD. They are active as AhR agonists in vitro and
in vivo when present at 10213 to 1029 M concentrations. The endogenous
tryptophan degradation product kynurenine and the synthetic molecule
CH223191, a commonly used AhR antagonist, bind to the AhR with lower
affinity (approximately 1026 M) (Kim et al., 2006; Opitz et al., 2011).
Based on their lack of planarity and different size compared with the
high-affinity agonists TCDD, FICZ, and ICZ, it is most likely that their
interactions with the AhR also involve other mechanisms. CH223191,
2-methyl-2H-pyrazole-3-carboxylic acid(2-methyl-4-o-tolylazo-phenyl)-amide.
stimuli and then become essential for downstream differentiation events. There are still many unknowns, which
need to be solved before starting therapeutic manipulation
of the receptor in a cell-specific manner. A summary of the
current knowledge regarding AhR expression levels in
immune cells is displayed in Fig. 3.
Mouse models with no or modified AhR signaling
have been generated and are used in studies of the
immune system (Esser, 2009), and data emerge also
from newly bred conditional mouse lines in which AhR
deficiency is restricted to certain cells (Kiss et al., 2011;
Di Meglio et al., 2014). AhR deficiency and AhR dysregulation by xenobiotics have considerable consequences
for barrier tissue development and function of cells of the
adaptive and innate immune system. For example, mice
with a constitutively active AhR in keratinocytes are
afflicted with inflammatory skin diseases (Tauchi et al.,
2005). Together, the findings argue strongly for the view
that AhR is an evolutionary shaped, signaling pathway for physiologic immune functions. In the immune
system, it balances and integrates environmental cues
into an appropriate immune response.
B. Aryl Hydrocarbon Receptor in the Skin
The skin offers protection from environmental stresses
such as dehydration, UV light, mechanical trauma, and
infections. The skin is a layered organ, with the epidermis
on top, the much thicker dermis underneath, and finally
the subcutis as the innermost layer. Blood and lymphatic
vessels reach into the dermis and serve as ports for
emigrating and immigrating immune cells. Resident
immune cells are interspersed in both the dermis and
epidermis.
1. The Dermis. The dermis has high cell diversity;
the structural cells are the fibroblasts, which secrete
matrix proteins and hyaluronic acid. Interspersed among
the fibroblasts are macrophages, mast cells, dendritic
cells (DCs), and many T cells, all with differing levels of
AhR expression (Esser et al., 2013). For humans, it has
265
been estimated that more T cells are in the skin than in
the blood (Clark et al., 2006). Dermal fibroblasts express
the AhR at high levels. Interestingly, they upregulate
matrix metalloproteinase-1 but do not upregulate CYP1A1
upon AhR ligand exposure. The former result relates to
the role of AhR in UV-mediated skin aging (Ono et al.,
2013; Tigges et al., 2014), whereas the latter has been
interpreted as a protection against generation of reactive
oxygen species in these mostly postreplicative cells.
2. The Epidermis. The structural cells of the epidermis are the keratinocytes, which differentiate from the
innermost stem cell layer to the outer stratum corneum
layer, with enucleated corneocytes forming a water-tight
final barrier. Keratinocytes gain AhR and CYP1A1
expression along this “outward” differentiation (Jones
and Reiners, 1997; Swanson, 2004). Interspersed in
the epidermis are approximately 5% Langerhans cells
(LCs, a subset of DCs) and, in mice, also approximately 5% dendritic epidermal T cells (DETCs, with
a skin-typical, invariant gd T-cell receptor (TCR) for
which the antigen specificity is not known). Together
with the keratinocytes, they form an immune network
with surveillance capacities (Jameson et al., 2004).
Similar to dermal fibroblasts, keratinocytes express
AhR; LCs, DETCs, melanocytes, sebocytes, and mast cells
also express AhR (Esser et al., 2013), as do tissue-resident
CD8+ memory T cells (Zaid et al., 2014). Interestingly,
a concomitant high constitutive expression of AhR repressor has been reported for LCs, DETCs, and fibroblasts
(Haarmann-Stemmann et al., 2007; Jux et al., 2009; Tigges
et al., 2013).
3. Aryl Hydrocarbon Receptor–Mediated Skin Functions.
It is commonly assumed that the high AhR levels in all
skin cell types serve some physiologic purpose (Ma,
2011). The search for such physiologic role(s) of AhR in
the epidermis is ongoing, using AhR overactivation on
the one hand and AhR-deficient mouse models on the
other hand. Studies involving AhR-deficient mice indicated that AhR is needed for proliferation of melanocytes and thus pigmentation (Jux et al., 2011). In humans,
epidemiologic studies strongly suggested that air pollution
from soot and traffic (which contains AhR ligands) is
correlated to increased extrinsic skin aging (Vierkötter
et al., 2010). Studies with topical or systemic application of
AhR ligands (e.g., TCDD or FICZ) demonstrated that AhR
signaling is involved in degranulation and cytokine production of mast cells (Sibilano et al., 2012) and differentiation of sebocytes (Ju et al., 2011). In keratinocytes, AhR is
involved in the UVB stress response (Fritsche et al., 2007)
and antiapoptotic signaling in response to UV (Frauenstein
et al., 2013). AhR presence in skin can protect against
UV-induced erythema or change the gene expression profile
of keratinocytes. Moreover, epithelial-to-mesenchymal
transition and motility of keratinocytes is enhanced in
AhR-deficient keratinocytes. Finally, AhR is involved
in UV-induced immunosuppression (Navid et al., 2013;
Rico-Leo et al., 2013; Bruhs et al., 2015).
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Esser and Rannug
Fig. 3. AhR expression levels in cells of the hematopoietic lineage. All cells of the immune system are derived from the HSC. HSCs differentiate and
branch out into further lineage precursor cells (the common lymphoid and common myeloid precursor). Differentiation is controlled intrinsically and/or
extrinsically such as by cytokines or antigen contact. This graph depicts the main lineages and immune cell subsets. Arrows indicate lineage
relationships. Cells behind brackets are different descendants of the cells before the bracket; note that no attempt at depicting detailed lineage
relationships was made. Especially for the ILCs, lineage relationships have not been finally worked out. AhR expression levels in cells of the
hematopoietic lineage are usually determined by quantitative polymerase chain reaction or Western blotting. It is difficult or not feasible to consolidate
results for different cell subsets from independent publications. For instance, in the article by Veldhoen et al. (2008), the different Th subsets were
compared side by side, indicating that Th17 cells had significantly higher levels than the other Th cell subsets, but in this study, expression levels of
DCs were not included. AhR expression in the liver is very high compared with other organs. However, some immune cells, such as gd T cells in the
skin, can express AhR even higher, as evident when both tissues are tested in the same experiment. Data displayed in the graph are taken from articles
cited in this review and in addition from Sherr and Monti (2013) for B cells and plasma cells. Asterisks (*) denote where it is known that AhR plays
a role as a transcription factor in lineage-specific differentiation or maturation. Plus signs (1) denote where AhR is known for a functional role in
expressing an effector function of the cell (e.g., cytokine secretion, IDO production or other functions). For details, see the text. CILP, common innate
lymphoid precursor; CLP, common lymphoid precursor; CMP, common myeloid precursor; GMP, granulocyte macrophage precursor; HSC, hematopoietic stem cell; i, invariant; IDO, indolamine 2,3-dioxygenase; NKT, natural killer like T cell; PC, plasma cell; trTm, tissue-resident memory T cell;
v, variant.
4. Aryl Hydrocarbon Receptor in Two Skin-Specific Innate
Immune Cells. DCs phagocytize antigens and process and
present them to T cells. In addition, they secrete cytokines
and factors, which provide a proinflammatory or immunosuppressive milieu, shaping the differentiation pattern
of T cells into inflammatory or regulatory subsets. LCs
are the resident DCs in the epidermis. In contrast with
dermal DCs, they presumably are tolerogenic by default
(Kaplan et al., 2008). LCs continuously sample skin
antigens and migrate to the nearest lymph node to
present their antigen to T cells. Studies in AhR-deficient
mice indicated that AhR is necessary for the maturation
of LCs and their antigen-presenting capacity (Jux et al.,
2009). Expression of maturation markers could be rescued by GMCSF, a cytokine also produced by DETCs,
which are lacking in AhR-deficient mice, as detailed below.
As a consequence, AhR-deficient mice do not mount a
strong contact hypersensitivity response when challenged
with chemical haptens, such as fluorescent isothiocyanate
or dinitrofluorobenzene.
DETCs are unconventional immune cells, with an
invariant gd TCR. As with all epithelial invariant gd
T cells, they are generated exclusively in a tight time
window in the fetal thymus. gd T cells secrete inflammatory cytokines quickly after antigen contact and are
pivotal in fighting bacterial infections and killing tumor
cells (Hayday et al., 1985; Girardi et al., 2002; Strid
et al., 2009). They are an important source of IL-17 and
IL-22, and thereby are also involved in autoimmunity
(Roark et al., 2008). DETCs are abundant in the murine
epidermis but not in the human epidermis. However,
humans have a similar population of gd T cells in their
dermis (Holtmeier and Kabelitz, 2005). Apparently, human
dermal gd T cells recognize stress-inducible molecules, such
Aryl Hydrocarbon Receptor in Immunology and Toxicology
as MICA/B, as well as other ligands. In mice, DETCs play
an important role in the control of inflammatory skin
reactions, in wound healing, and in cancer surveillance
(Strid et al., 2009). DETCs immigrate into skin shortly
before birth and expand by proliferation within a few weeks
thereafter. This expansion does not take place in AhRdeficient mice. Their skin niche remains empty (in contrast
with TCRd2/2 mice, for which gd T cells are never made,
and whose skin niche becomes filled with ab T cells).
Recent work has indicated that the newly recognized
CD8+ tissue-resident memory T cells, which persist
after a viral infection has been resolved, can replace
DETCs in the skin. By contrast, epidermal tissueresident memory T cells from AhR-deficient mice do not
persist in the epidermis after infection, highlighting
a role for the AhR in the competition for space and/or
appropriate contact with keratinocytes and LCs by
innate and adaptive T cells in the skin (Zaid et al.,
2014). The loss of DETCs and the functional impairment of LCs in AhR-deficient mice may lead to barrier
impairment. As indicated for the human epidermis,
activated AhR induces production of pivotal barrier
proteins by keratinocytes and accelerates epidermal
barrier formation in mouse fetuses (Sutter et al., 2011).
Accordingly, we have observed increased transepidermal water loss in AhR-deficient mice, congruent with
barrier impairment (C. Esser, unpublished data). Interestingly, an old and efficient therapy for atopic
dermatitis (AD) is treatment with medical coal tar, a
substance rich in AhR ligands. Barrier impairment
is a prominent feature of AD. It was demonstrated in
organotypic skin cultures from AD patients that coal tar
activated the AhR, induced epidermal differentiation,
restored filaggrin expression, and improved skin barrier
proteins in an AhR-dependent manner (van den Bogaard
et al., 2013).
In conclusion, the skin is a site of high AhR expression and high AhR ligand availability, and the
AhR is involved in many skin functions, including the
skin immune network and cell homeostasis. This can
be exploited pharmacologically. Examples are the use
of medical coal tar described above as well as the use of
AhR antagonists to protect from UVB-associated skin
cancer (Tigges et al., 2014).
5. High-Affinity Aryl Hydrocarbon Receptor Ligands
in the Skin. It is intriguing to think of skin-located,
abundant AhR ligands as evolutionary drivers of these
functions. In the skin, AhR ligands are formed in situ
by several sources. UV light generates the high-affinity
ligand FICZ from tryptophan. In addition, hydrogen
peroxide in skin of vitiligo patients can lead to formation
of FICZ (Schallreuter et al., 2012). Common skin-resident
yeasts, Malassezia spp., produce the AhR ligands
FICZ, ICZ, pityriacitrin, and malassezin (Wille et al.,
2001; Gaitanis et al., 2008; Magiatis et al., 2013). LCs
produce AhR-dependently the immunosuppressive enzyme
indoleamine 2,3-dioxygenase (Jux et al., 2009; Nguyen
267
et al., 2010), which converts tryptophan to kynurenines.
Kynurenines as AhR ligands thus enhance their own
production, generating an immunosuppressive micromilieu
in the skin (Mezrich et al., 2010; Nguyen et al., 2010).
Kynurenines can also induce regulatory T cells (Tregs)
directly (Mezrich et al., 2010). In addition, AhR activators
can be present in topically applied cosmetics, creams, or
drugs.
C. Aryl Hydrocarbon Receptor in the Gut and
Consequences for Gut Health and Microbiome
1. The Gut-Associated Immune System: A Paradigm
of Immune Activation and Suppression. The gut is not
only in contact with dietary compounds but is also a site
of contact with numerous organic and inorganic environmental compounds. The small and large intestines
harbor a highly diverse microflora; in humans, it is
estimated that approximately 1014 bacteria live in the
gut. Many of them are from the phyla firmicutes (65%)
and bacteroidetes (30%) (Qin et al., 2010). Of note,
food—its proteins, carbohydrates, and lipids—is a rich
source of potential antigens, and immune responses
against food constituents can lead to allergies and
intestinal inflammation. It is thus vital that the gutassociated immune system protects against infection
while it maintains tolerance against harmless antigens.
The gut-associated immune cells specialize in this dual
task. The gut content is separated from the inner body
only by a single epithelial cell layer of intestinal epithelial cells (IECs) and a mucus layer secreted by goblet
cells. The gut epithelium allows passage of nutrients
from the lumen into the blood stream, and the mucus
has important functions in protecting the integrity of the
epithelium. Interspersed among the IECs are intraepithelial lymphocytes (IELs), many of them invariant gd
T cells, others abTCRCD8aa+ T cells. Underneath the
epithelium, in the lamina propria, more immune cells
reside, especially DC subpopulations and innate lymphoid cells (ILCs). Breakage of the intestinal barrier
results in potentially deadly inflammation and sepsis.
2. Aryl Hydrocarbon Receptor in Innate Immune
Cells of the Gut. Excitingly, a reciprocal relationship
between gut bacteria and their metabolites and the gut
immune system exists, in which the AhR also plays a
role. AhR-deficient RORgt+ ILCs (a major source of
intestinal IL-22) have reduced IL-22 expression; therefore, AhR-deficient mice easily succumb to Citrobacter
rodentium infection (Qiu et al., 2013). Qiu et al. (2013)
indicated that treatment with FICZ (0.5 mg/kg) significantly increased the accumulation of RORgt+ ILCs
in AhR+/2 or AhR+/+ mice but not in AhR2/2 mice. In
another study, Zelante et al. (2013) analyzed lactobacillus species (nonpathogenic gut bacteria) and presented
evidence that these bacilli can generate AhR ligands in
the gut, such as indole-3-aldehyde, from tryptophan and
thereby enhance AhR-dependent IL-22 production. In a
reporter assay, indole-3-aldehyde induced AhR-dependent
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Esser and Rannug
transcription but only at high concentration, suggesting
that it is a low-affinity ligand. However, indole-3acetaldehyde, one of the products formed together with
indole-3-aldehyde, can produce the high-affinity ligand
FICZ (Rannug et al., unpublished data), and this could be
relevant for the effects observed by Zelante and colleagues.
IL-22 acts on epithelial cells and induces their production
of antimicrobial peptides (e.g., RegIIIg) and stimulates
tissue regeneration. As a result, commensal bacteria
might outcompete pathogenic bacteria and prevent
colonization with the fungus Candida albicans (Zelante
et al., 2013). Similar to the situation in skin keratinocytes
and skin immune cells, the AhR is expressed highly in
IECs and in cells of the gut-associated immune system.
AhR-deficient mice have highly reduced IEL numbers in
the small intestine (Chmill et al., 2010; Li et al., 2011;
Nakajima et al., 2013), which is associated with reduced
levels of IL-22 and thus a reduction of the antimicrobial
peptides RegIIIb and RegIIIg (measured in the ileum)
and a higher microbial load in both the small intestine
and colon (Li et al., 2011). The loss of IEL is cell intrinsic,
because AhR-deficient bone marrow cells did not reconstitute the intestine in Rag2/2 mice (Li et al., 2011).
Moreover, in the gut of AhR-deficient mice, subsets of
ILC3s (Spits et al., 2013), ILC22 and CD32NKp46+
lymphoid tissue inducer cells, are lost over time after
birth (Kiss et al., 2011; Lee et al., 2012). Again, failure of
ILC3 to proliferate in AhR-deficient mice is an intrinsic
effect, because the AhR is needed to transcribe a cellspecific proliferation factor, c-kit (Kiss et al., 2011; Lee
et al., 2012). As a consequence, no secondary lymphoid
structures, such as cryptopatches or innate lymphoid
follicles, are formed in the intestine of AhR-deficient
mice, and they become susceptible to C. rodentium
infection (a model for attaching and effacing Escherichia
coli EHEC in humans). ILC3s are characterized by IL-17
and IL-22 secretion (Diefenbach, 2013; Spits et al., 2013).
AhR-deficient mice are not only more susceptible to
C. rodentium infection, they are also more susceptible to
dextran sodium sulfate (DSS)–induced murine colitis.
DSS damages gut epithelial integrity and causes inflammation and bacterial dissemination. AhR-deficient
mice constituted with wild-type IELs did not succumb to
DSS colitis, demonstrating the importance of IELs in
reducing the damage (Lee et al., 2012).
3. Systemic Effects of Oral Aryl Hydrocarbon Receptor Ligand Exposure. The role of the AhR on cells
of the adaptive immune system, especially on T cells,
was also reviewed in Pharmacological Reviews (Quintana
and Sherr, 2013). As reviewed there, mice generate
protective Tregs if treated orally with the AhR agonist
ITE (originally isolated from swine lung) before subjecting them to a protocol of immunization with myelin
oligodendrocyte glycoprotein MOG35–55 to induce experimental allergic encephalitis (Gandhi et al., 2010;
Quintana et al., 2010). The authors concluded that ITE
mediates the effect by inducing CD103+ DCs in the gut,
which then support Treg generation. In another study,
however, it was found that TCDD exposure of mice
impaired the capacity to establish stable oral tolerance
against a food antigen (Chmill et al., 2010), presumably
by inducing an inflammatory state with higher levels of
IL-6 secretion in gut-derived DCs. It is possible and likely
that AhR ligands as such (affinities, degradability, etc.)
as well as the exposure regimens are decisive in the
outcome for the tolerogenicity versus immunogenicity
balance in the gut (Duarte et al., 2013).
4. Role of Dietary Ligands in Development of the
Innate Gut Immunity. Dietary AhR ligands are necessary for constitutive CYP1A1 levels and induction in the
gut (Ito et al., 2007). An intriguing set of experiments
demonstrated the role of dietary AhR ligands for innate
immune cell homeostasis in the gut. Experimental mouse
diets are for the most part grain based and contain high
concentrations (up to several grams per kilogram) of AhR
activators, such as polyphenols and glucosinolates.
Colonies of mice were fed with a synthetic diet of very
low AhR activator content, and then newborn mice were
analyzed 3 to 4 weeks after birth. Mice had a similar
phenotype as AhR-deficient mice: low-level c-kit expression, low ILC3 numbers, and because of ILC3’s tissue
inducer capacity, no formation of proper cryptopatch
clusters and isolated lymphoid follicles (Kiss et al.,
2011). The frequency of lamina propria lymphocytes did
not change at this early stage. The phenotype could be
rescued by adding the proligand I3C, which is converted
to the high-affinity ligand ICZ in the acid milieu of
stomach, to the diet in wild-type but not AhR-deficient
mice, indicating that both ligand and the AhR are
necessary for development of the innate gut immune
cells. However, removal of AhR activators from the diet
once the ILC3s are established (approximately 6 weeks
after birth) had no effects on their further homeostasis.
In another experiment, feeding adult mice for 3 weeks
with a synthetic diet low in AhR activators reduced
cyp1a1 expression in the intestine and led to a significant decrease in IEL (both gd T cells and ab TCR/
CD8aa+ T cells). Again, addition of I3C rescued the
phenotype (Li et al., 2011). It is not known what the
minimal levels of AhR activators in the diet are, which
might be needed for a “healthy” gut, because doseresponse experiments have not been performed. However, the results assert the need for the presence of
distinct noncaloric micronutrients in the diet, both for
formation of innate lymphoid follicles after birth and for
homeostasis of IELs later. In a note of caution, it is also
not known at what dose “too much of a good thing”
would occur. For example, the induction of CYP1A1, or
ensuing reactive oxygen species formation, could lead to
adverse health effects. Experiments in mice indicated
that TCDD could cause a loss of oral tolerance against
food proteins (Chmill et al., 2010). In another setting,
feeding of encapsulated AhR ligand ITE improved experimental autoimmunity (Yeste et al., 2012). This
Aryl Hydrocarbon Receptor in Immunology and Toxicology
suggests that AhR activation in the gut by environmental pollutants or possibly even food additives can have
both adverse and beneficial effects on oral tolerance.
Both findings—the importance of AhR signaling for
the development of innate immune cells and for oral
tolerance—have potential therapeutic applications. Plantderived compounds may be used in the future to
therapeutically address diseases such as necrotizing
enterocolitis of preterm infants (Neu and Walker, 2011) or
inflammatory diseases of the gut. In addition, enhancement of oral tolerance might be useful in therapies
whereby autoantigen is given orally to dampen autoimmunity (Thurau et al., 2004; Yeste et al., 2012).
D. Aryl Hydrocarbon Receptor in the Lung
Lung epithelial tissue, similar to the gut, is a monolayer of cells. Several subsets, including the basal stem
cells, the ciliated cells, the goblet cells (for mucus
production), and the brush cells, line the airways; the
epithelium and its mucus layer become thinner toward
the alveoli. Underneath the epithelium is a basal matrix
in which immune cells are found (mast cells, lymphocytes, DCs, and ILC groups 1, 2, and 3). Lung tissue
expresses the AhR at high levels (Li et al., 1994; Frericks
et al., 2007).
The lung is exposed to AhR activators present in
airborne particulate matter from charcoal or wood burning,
industrial exhausts, car emissions, cigarette smoke, or
urban dust. PAHs are often part of air pollution particulate
matter and have existed as environmental agents long
before industrialization. Particulate matter has different
effects depending on chemical composition as well as size,
with nanoparticles (defined as 1–100 nm in diameter) even
capable of entering cells and the nucleus (Hemmerich and
von Mikecz, 2013). AhR expression by lung epithelium
allows detection and metabolic elimination of unwanted
xenobiotic pollutants through induction of CYP1 enzymes.
Another (mechanical) possibility is the regulation of mucus
secretion; the genes for MUC5B and MUC5AC could be
targeted by the activated AhR in a lung epithelial cell line
(Wong et al., 2010; Chiba et al., 2011). In vivo mucus
production enforces the physical protection of the lung
epithelium. In another study, the AhR was demonstrated
to protect fibroblasts from apoptosis caused by cigarette
smoke (Rico de Souza et al., 2011). At the same time, AhR
activity could be an integral part of a balanced immune
response in the lung. For example, exposure to airborne
particles (urban dust, diesel exhaust, cigarette smoke) via
intranasal administration was shown to increase IL-17
expression in the lung of C57BL/6 mice (van Voorhis et al.,
2013), and evidence emerges that IL-17 is important in
lung diseases in both humans and mice (Ivanov et al.,
2005).
Epidemiologic studies have linked exposure to air
pollution to immunologic diseases of the respiratory
system, such as asthma and chronic obstructive pulmonary
disease (COPD), innate immune cells, and polymorphisms
269
of inflammatory cytokines (Morgenstern et al., 2008;
Vawda et al., 2014; Yu et al., 2014). To link air pollution
to these lung diseases, experimental exposures to AhR
ligands, AhR-deficient mice, and various infection or
lung damage models are used to identify underlying
mechanisms and the role of the AhR.
1. Lung Inflammation. Lung inflammation can be
caused by AhR activators, such as those present in
cigarette smoke. Studies in AhR-deficient mice demonstrated that exposure to cigarette smoke for only
a few hours on 3 consecutive days before euthanasia
enhanced neutrophil influx and levels of inflammatory
cytokines IL-6, macrophage inflammatory protein 2,
and prostaglandin E2 and increased tissue damage
(Thatcher et al., 2007). The contribution of innate versus
adaptive immune cells to lung pathology is still under
investigation, and many inflammatory mediators have
been implicated as well. Macrophages, cells critical for
the development of inflammatory processes, express the
AhR and can be activated by TCDD to produce modulatory
chemokines or release proinflammatory cytokines (Vogel
et al., 2007).
2. Respiratory Viral Disease. The AhR is a modulator of antiviral immunity in the lung. In particular, the
work by the group of Paige Lawrence demonstrated the
complex relationship of AhR-mediated events in CD8
T cells, DCs, neutrophils, and lung epithelium in influenza
A virus–infected mice (Vorderstrasse et al., 2003; Jin
et al., 2014). AhR activation by TCDD decreased survival
from infection with a nonlethal dose of influenza A virus
(Vorderstrasse et al., 2003), accompanied by doubled
pulmonary neutrophil influx and suppression of expansion and differentiation of virus-specific effector CD8+
T cells (Lawrence et al., 2006). At the same time, AhR
activation decreased the immunostimulatory function of
DCs in lung-draining lymph nodes and reduced their
frequency in the lungs (Wheeler et al., 2013; Jin et al.,
2014). Neutrophil influx is mediated by the AhR in the
lung epithelium because conditional AhR-deficient mice
(lacking the AhR only in lung epithelium) had no
increased neutrophil influx upon TCDD exposure. Both
TCDD and FICZ could modulate the anti–influenza
A response, although FICZ only affected CD8+ cells
(Wheeler et al., 2014). Together, the data in mice highlight
again that the AhR is used in a barrier organ to
orchestrate an appropriate immune response. It can,
however, become unbalanced by persistent and high
activation. It is thus no surprise that epidemiologic
evidence found that exposure to environmentally derived AhR activators correlates with increased respiratory infections (Del Donno et al., 2002).
3. Lung Fibrosis. Similar to the skin and the gut,
the murine lung harbors a unique population of invariant
gd T cells (Vg6/Vd1), which are one source of IL-22
production. Mice with either no gd T cells or with the
low-affinity AhR d-allele mount reduced IL-22 levels
in the lung upon Bacillus subtilis infection, leading to
270
Esser and Rannug
more fibrosis. Administration of IL-22 improves lung
inflammation and collagen deposition (Simonian et al.,
2010). Together, the data demonstrate that protective
IL-22 expression in this inflammation-induced pulmonary fibrosis is AhR dependent. Of note, unlike in the
skin or the gut, gd T cells do not disappear from the lung
in AhR-deficient mice (Simonian et al., 2010), indicating
that intrinsic proliferation requirements and/or intercellular interactions are different in the lung tissue than
in skin and gut.
IV. The Aryl Hydrocarbon Receptor in
Toxicology and Physiology of the Human Skin,
Lung, and Gut
Species differences in TCDD toxicity and AhR signaling are well known. It is important to understand AhR
signaling in human biology, both for toxicology and for
any possible therapeutic use of the AhR and its ligands.
Research draws on results from epidemiology, accidental
environment exposures, tissue culture, and patient studies.
In this section, we address some AhR events typical for
human barrier organs and stem cells that go beyond
immune functions.
In contrast with some animals, in which dioxins can
cause death after even tiny doses, dioxin-like compounds
are not acutely toxic/deadly in humans even at high
exposures, and skin is often the main organ that is
affected by PHAHs. Chloracne, hyperpigmentation, and
thickening of the skin on palms and soles have been
reported after exposure to a number of dioxin-like agents.
Chloracne, the hallmark of dioxin toxicity in humans, is
characterized by epidermal hyperplasia, disappearance
of sebaceous glands, and multiple epithelial cysts, which
are now described as hamartomas (Saurat et al., 2012).
The same pathologic responses to TCDD, including
hyperkeratosis, epidermal hyperplasia, sebaceous gland
involution, and intraepidermal keratinous cysts have
earlier been described in mice homozygous for mutations
in the hairless gene (hr/h) but not in other naked mice
(Puhvel et al., 1982). The hairless protein is now known
to be a nuclear receptor corepressor that regulates hair
regeneration by interacting with Wnt/b-catenin signaling
(Beaudoin et al., 2005). Because the sebaceous gland and
hair follicle epithelium have the same cellular source for
renewal, chloracne is now suggested to be caused by a
switch from a sebaceous to epidermal type of differentiation mediated through transient activation of the
nuclear protooncogene c-Myc, which is a target of the
Wnt/b-catenin pathway (Panteleyev and Bickers, 2006;
Saurat et al., 2012). A recent study with TCDD treatment of human skin samples exposed ex vivo and
cultured human SZ95 sebocytes supports this suggestion.
The authors show TCDD- and AhR-dependent shrinkage
of sebaceous glands with a switch of sebaceous into
keratinocyte-like differentiation, eventually by targeting
sebaceous progenitor cells (Ju et al., 2011). In addition,
hyperpigmentation of human skin and gingiva has been
observed after exposure to both PAHs and PHAHs (Urabe
and Asahi, 1985; Haresaku et al., 2007; Nakamura et al.,
2013). The mechanisms behind AhR-mediated pigmentation were first described by us (Luecke et al., 2010; Jux
et al., 2011) and were recently further elucidated by
Nakamura et al. (2013). They provide evidence for
involvement of both AhR and Wnt/b-catenin signaling
in tobacco smoke extract–induced melanocyte activation
(Nakamura et al., 2013). In addition, hyperkeratotic
skin conditions have been reported in humans exposed
to dioxins (Geusau et al., 2000). Correct palmoplantar
keratinization depends on intact Wnt/b-catenin signaling,
and palmoplantar keratoses are seen in humans that
carry mutations in the gene coding for R-spondin, an
agonist of Wnt/b-catenin signaling (de Lau et al., 2012).
Induction of the AhR target gene CYP1A1 has been
repeatedly documented in human skin and cultured
human keratinocytes. For instance, increased benzo[a]
pyrene hydroxylation capacity was observed in skin from
coal tar–treated patients with dermatological diseases
(Bickers and Kappas, 1978). UV light induces CYP1A1 in
human skin (Katiyar et al., 2000) and cultured human
keratinocytes (Wei et al., 1999; Fritsche et al., 2007).
Furthermore, the proposed endogenous AhR ligand FICZ
has been detected in UVB-irradiated immortal human
keratinocytes (Fritsche et al., 2007), in skin samples from
vitiligo patients (Schallreuter et al., 2012), and in skin
from patients with seborrheic dermatitis carrying commensal yeasts belonging to the genus Malassezia, which
converts tryptophan to several AhR-activating compounds (Magiatis et al., 2013).
There are also systemic manifestations, which have
been attributed to the exposure to PHAH in humans
exposed in environmental accidents and at the workplace and for human volunteers (Suskind, 1985; Aoki,
2001; Saurat et al., 2012). Chronic bronchitis–like symptoms were observed in over 60% of Yusho patients that had
been exposed to cooking oil contaminated with polychlorinated biphenyls and very potent AhR ligands of the
polychlorinated dibenzofuran type (Aoki, 2001). Epidemiologic reports from the 1976 Seveso accident in Italy
have associated TCDD exposure with a more than doubled
incidence of COPD (Consonni et al., 2008). COPD affects
approximately 200 million people worldwide and is
globally one of the leading causes of death. The disease
starts with inflammation, influx of macrophages and
neutrophils, and oxidative stress, which exacerbates
inflammation (Roca et al., 2013). Smoking, biomass
burning, air pollution, and inhalation of fine dust are
causative agents (Brunekreef and Forsberg, 2005). Atmospheric particulate matter—known to be carriers of AhR
ligands—aggravates COPD. Further understanding the
role of the AhR in COPD is an important area for future
research (van Voorhis et al., 2013).
Furthermore, nausea, vomiting, gastritis, and colitis
with multiple ulcers have been documented in many
Aryl Hydrocarbon Receptor in Immunology and Toxicology
epidemiologic studies of PHAH-exposed groups (Kuratsune
et al., 1972; Suskind, 1985; Urabe and Asahi, 1985). In
addition, the dioxin-poisoned former Ukrainian president
Yushchenko initially suffered from severe gastritis (Saurat
et al., 2012). A study performed with nonhuman primates fed chlorinated biphenyls and triphenyls indicated
hyperplasia and dysplasia of the gastric mucosa with
replacement of the gastric acid–secreting parietal cells
by mucus-secreting cells (Allen and Norback, 1973). Interestingly, constitutively active AhR causes similar
gastric lesions in mice, including gastric hamartomatous
tumors (Andersson et al., 2005).
These and other findings indicate important roles of
the AhR in rapidly renewing human tissues and
demonstrate key roles for interactions with the Wnt/
b-catenin pathway, which seem to explain the skin disorders, including chloracne, that occur in humans exposed
to TCDD.
A compilation of the facts described in sections III
and IV is displayed in Fig. 4.
V. The Aryl Hydrocarbon Receptor: Promiscuous
Sensing of Chemicals or Metabolic Control of the
Endogenous High-Affinity Ligand FICZ?
From the evidence reported above and many other
studies, it is evident that numerous chemicals can
interfere with the AhR signaling system. From this, it
was concluded that the AhR is a promiscuous sensor of
small chemicals; in other words, even low-affinity small
chemicals affect physiologic functions through binding
and activation. We think that the evidence is not conclusive, first, because the very low affinity of many such
putative ligands is not sufficiently taken into account; and
second, because the presence of the high-affinity ligand
FICZ, omnipresent under cell culture conditions and
probably in all tissues, has to be considered in the
interpretation of the data. An influence on the metabolic
turnover of the endogenous ligands could be a major
reason for the dysbalance observed with factors that
induce or inhibit the activity of CYP1 enzymes (Fig. 5).
The receptor is highly selective for molecules having
certain characteristics constricted by size, lipophilicity,
and shape. A view that the AhR has few endogenous
ligands is supported by the fact that the AhR is
evolutionary conserved and that the protein is present
even in the most primitive vertebrate species. This
suggests that it has a fundamental role in cellular
physiology. In addition, several results from studies
with AhR knockout mice have demonstrated functions
that need the AhR under developmental stages and
for physiologic homeostasis processes without exogenously administered ligands (Gasiewicz et al., 2014).
According to what is now known about FICZ, ICZ,
and possibly ITE and other indoles, these molecules seem
to fulfill the role of endogenous ligands that maintain
important functions in biologic systems (Ma, 2011). In
271
particular, FICZ binds to the AhR with the highest
affinity yet reported (Rannug et al., 1987; Nguyen and
Bradfield, 2008). FICZ also binds to frog and bird AhRs
where TCDD is relatively inactive. This indicates evolutionary conservation of the FICZ response in TCDDinsensitive species, suggesting its physiologic importance
as an AhR ligand (Laub et al., 2010). FICZ and ICZ
are also efficiently autoregulated by the induced CYP1
enzymes (Wei et al., 2000; Bergander et al., 2004; Wincent
et al., 2009). In fact, the catalytic efficiency of CYP1A1 for
FICZ is close to the limit of diffusion (Wincent et al., 2009).
FICZ has been identified in human skin (Wincent et al.,
2009; Schallreuter et al., 2012; Magiatis et al., 2013), and
FICZ-derived sulfate conjugates have been detected in
human urine (Wincent et al., 2009). The current data
suggest that FICZ can be formed via different pathways that lead to formation of indole-3-acetaldehyde,
the precursor of FICZ, such as enzymatic deamination
of tryptamine and oxidation of tryptophan by intracellular
oxidants (Rannug et al., unpublished data). Occurrence of
ICZ may be restricted to the gut. It is entirely conceivable
that there are more ligands with similar chemical
structures that are capable of fulfilling AhR-regulated
functions in a tissue-specific manner.
The important role of efficient control over the metabolic
turnover of FICZ is illustrated by recent data suggesting
that FICZ can stimulate various signaling pathways
and thereby affect critical and specific cell functions (see
Table 2).
It is now well recognized that unintended, ill-timed,
or prolonged activation of the AhR by many exogenous
small molecules may lead to expression, synthesis, and
activity of many proteins. This in turn may disturb tightly
controlled and transient physiologic functions (Mitchell
et al., 2006; Stockinger et al., 2014). This seems to explain
the toxicity of TCDD, which is unmatched by any other
human-made substance. This fact has to be considered
when trying to identify pharmacological agents with
therapeutic potential by interfering with AhR signaling
because they may disturb such tightly controlled and
transient signals and lead to unwanted toxicity. The
growing knowledge about factors that interfere with
AhR signaling and the high specificity and flexibility,
however, demonstrates ample possibilities for preventive actions.
VI. Therapeutic Potential of Aryl Hydrocarbon
Receptor Ligands
The therapeutic potential of the AhR has been recognized early, especially in the context of cancer (Safe et al.,
1999, 2013). The effects of AhR ligands as agonists or
antagonists are dependent on several factors including
ligand structure, specific gene, and cell context–dependent
expression of important cofactors or coactivators. Thus,
selective aryl hydrocarbon receptor modulators (SAhRMs)
have been developed with a view to clinical applications
272
Esser and Rannug
Fig. 4. Summary of involvement of AhR signaling in skin, gut, and lung epithelial barrier functions and barrier immunity as they are currently known.
In the skin and gut, epithelium immune cells (DCs and specialized T cells) are integrated. In the lung, immune cells are not interspersed but can be
recruited. The little cartoons indicate this. For details and references, see the text. AhR is highly expressed in epithelial and various immune cells of
skin, gut, and lung. Endogenous functions of AhR signaling were unraveled through work with either AhR-deficient (full or conditional) mice or by
experimentally activating AhR signaling in healthy or diseased situations. In general, AhR signaling must be leveled appropriately to avoid either
toxicity or immunologic impairment.
(Safe et al., 2013). For instance, 12 weeks of feeding
6-methyl-1,3,8-trichlorodibenzofuran inhibited metastasis
in a mouse model of prostate tumorigenesis, in part
by inhibiting prostatic vascular endothelial growth factor
production prior to tumor formation (Fritz et al., 2009).
SAhRMs aim to modify AhR activation in such a way that
the beneficial effects outweigh toxic effects (e.g., those
known from dioxins). The complexity of AhR signaling
outcomes is evident from the above sections. There are
several obstacles. First, an AhR ligand or proligand might
be rapidly metabolized, and both the original compound
and metabolites may be involved in activities independent
of AhR signaling. In particular, this is true for antioxidants, such as resveratrol and quercetin. Other compounds are prone to formation of DNA adducts or protein
adducts, which may cause adverse effects. An example
of this is glucosinolates, which form DNA adducts
(Schumacher et al., 2014). The overall efficiency of a
SAhRM will depend on its chemistry and on multiple
factors including the dose, pharmacokinetics, absorption,
persistence, and other properties that must be considered
for development of a new pharmaceutical. For example,
poor absorption limits the effectiveness of the AhR ligand,
GNF351 (Fang et al., 2014), which exhibited promising
anticancer properties in head and neck cancer cells in
culture (DiNatale et al., 2012). Yeste et al. (2012) investigated the delivery to the gut of the ligand ITE, when
ITE was packed in nanoparticles (Yeste et al., 2012). Indeed,
this approach may enhance bioavailability.
Two other sources of AhR ligands with pharmaceutical potential are currently considered. First, various
dietary phytochemicals were identified as potential
ligands. Phytochemicals are non-nutrient plant compounds, which can be classified into phenolic compounds,
terpenoids, alkaloids, phytosterols, and carotenoids.
Phytochemicals are absorbed, metabolized, and effluxed
into the blood stream by IECs. Biotransformation is
catalyzed by enzymes controlled by the AhR battery, the
cytochrome P450s and phase II enzymes. For a number
of polyphenols, especially the large group of flavonoids,
immunomodulation and AhR activation were demonstrated (Denison and Nagy, 2003; González et al., 2011).
Second, AhR ligands are generated in cells and can be,
for example, products of amino acid metabolism. The
tryptophan-derived ligand FICZ is discussed above in
detail. Other tryptophan derivatives, the kynurenines,
and further downstream products such as the newly
identified cinnabarinic acid (stimulates IL-22) display
273
Aryl Hydrocarbon Receptor in Immunology and Toxicology
Fig. 5. Hypothetical schemes of FICZ homeostasis changes by unbalanced AhR and cytochrome P450 activity. (A) The high-affinity AhR ligand FICZ is
constantly produced in the organism. It induces CYP1A activity, which in turn degrades FICZ, thereby creating a homeostatic level of FICZ. (B) Other,
high-affinity AhR ligands, in particular the nondegradable TCDD, or very high concentrations of low-affinity AhR ligands can compete for AhR binding,
resulting in constantly high CYP1A activity and depletion of FICZ. (C) AhR activation can also occur by factors that block/inhibit CYP1A, leading to
exceptionally high FICZ levels because FICZ is no longer degraded. In both scenarios (B) and (C), FICZ homeostastic levels are changed, and
aberrant transcription of many genes could occur. The events would be similar for other endogenous high-affinity homeostatic ligands, such as ICZ
in the gut.
large potential as well (Mezrich et al., 2010; Lowe et al.,
2014). Although global gene expression profiles and
promoter studies have shed some light on the activities
of SAhRMs, AhR antagonists and agonists, and selective modulators for other receptors (Sun et al., 2004;
Nohara et al., 2006; Suzuki and Nohara, 2007; Nault
et al., 2013), the factors important for the selectivity of a
specific AhR ligand are not well understood and require
further investigation.
One example highlights the complexities of using
AhR ligand in therapy. With regard to the immune
system, the capacity of AhR agonists to shift the balance
between inflammatory, autoimmune-prone Th17 responses
and immunosuppressive responses driven by Tregs is of
considerable interest. Among the Th cell subsets, only Th17
cells express AhR at high levels. Under in vitro Th17
differentiating culture conditions, AhR ligands (even low
amounts of FICZ produced by light from tryptophan
present in cell culture medium) promote the generation
of the Th17 phenotype, including secretion of IL-17 and
IL-22. It was thus unexpected that in mice in vivo, the
severity of two crippling autoimmune diseases (experimental allergic encephalitis or experimental allergic
arthritis) as well as inflammatory colitis, decreased upon
exposure to TCDD, ITE, or FICZ (Quintana et al., 2008;
Monteleone et al., 2011; Nakahama et al., 2011). Autoimmunity is driven by Th17 cells and ameliorated or
prevented by antigen-specific regulatory T cells. In the
TABLE 2
Biologic functions demonstrated to be influenced by FICZ
References
Biologic End Point
In Vitro
Antitumor activity
Cell growth and expression of
growth factor genes
Circadian rhythmicity
Expression of AhR target genes
Genome rearrangement
Immune response
Nuclear receptor cross-talk
Du et al., 2005; Fritsche et al., 2007; Kostyuk et al., 2012;
John et al., 2013
Wei et al., 2000; Oberg et al., 2005; Sciullo et al., 2008; Nair
et al., 2009; Wincent et al., 2009; Lee et al., 2010; Luecke
et al., 2010; Mohammadi-Bardbori et al., 2012; Rico-Leo
et al., 2013; Sumida et al., 2013
Okudaira et al., 2010, 2013
Apetoh et al., 2010; Bankoti et al., 2010
Ekins et al., 2008; Reschly et al., 2008; Bunaciu and Yen,
2013
In Vivo
Shin et al., 2013
Smith et al., 2013
Mukai and Tischkau, 2007
Jönsson et al., 2009; Laub et al., 2010; Wincent
et al., 2012; Odio et al., 2013
Quintana et al., 2008; Veldhoen et al., 2008;
Martin et al., 2009; Monteleone et al., 2011;
Jeong et al., 2012; Pauly et al., 2012; Qiu et al.,
2012; Sibilano et al., 2012; Duarte et al., 2013;
Wheeler et al., 2013; Zhou et al., 2013
274
Esser and Rannug
TABLE 3
AhR agonists suggested as potential therapeutic agents built on evidence from cell culture or animal studies
Name of Agonist or Antagonist
Cell/Animal
Studies
Disease Involved
Human
Trials
E/Z-2-Benzylindene-5,6-dimethoxy-3,
3-dimethylindan-1-one
6-Methyl-1,3,8-trichlorodibenzofuran
(a so-called selective AhR modulator)
Tranilast
Leflunomide
6,29,49-Trimethoxyflavone and GNF351
Sulindac, leflunomide, 4-hydroxytamoxifen,
mexiletine, and omeprazole
VAF347
UVB-induced skin damage (cancer,
skin aging)
Breast cancer, prostate cancer,
metastasis, lung cancer
Breast cancer
Melanoma
Head and neck cancer
Cancer, bone preservation
Aminoflavone
Breast cancer, renal cancer
Phase II
ITE
FICZ
Autoimmunity
Irritable bowel disease
No
No
Inflammation, transplant acceptance,
IL-22 induction
Cells
10 volunteers Tigges et al., 2014
Cells
No
Cells, animals No
Cells
No
Cells
No
Cells
No
Cells, animals
Animals
Human cells,
animals
Kynurenine inhibitor
Glioblastoma
Human cells
FICZ, kynurenine, and 3,39-diindolylmethane NK cell antitumor activity
Cells, animals
StemRegenin 1
Expansion of hematopoietic stem cells Cells
Coal tar
AD
Skin cultures
same studies, an amelioration of experimental allergic
encephalitis and experimental allergic arthritis was
reported for AhR-deficient mice or for AhRd/d mice
(which express a low-affinity AhR allele), adding further
to the puzzle. Originally, the phenomena were explained
by an induction of Tregs, but reports on direct FoxP3
induction by TCDD in vivo and in vitro are conflicting
(Quintana et al., 2008; Duarte et al., 2013), and no
enhancement of Tregs was evident in mice engineered
to have a constitutively active AhR in T cells (Quintana
et al., 2008; Funatake et al., 2009). DCs provide the
milieu for T-cell differentiation in vivo, and AhR
activation is involved in their tolerogenicity (Hauben
et al., 2008; Nguyen et al., 2010). Conceivably, the
situation in vivo integrates AhR activation in a more
complex fashion than deduced from in vitro data, and
in vitro data must be viewed with caution (Duarte
et al., 2013).
Although more data are needed, it is evident that
different AhR ligands were beneficial in the experimental model autoimmune diseases. In Table 3, we
have listed diseases for which AhR agonists/antagonist
have demonstrated promising results in cell or animal
studies and which have been suggested as having
potential for clinical applications. Many substances and
procedures are already protected by patents; however,
only few clinical trials exist thus far. Of note in this
context, there are drugs that had been approved for
human use (thus need no toxicity evaluation in clinical
trials) long before their appreciation as AhR agonists or
antagonists. Omeprazole and tranilast are examples that
are currently under investigation for new applications in
the context of their AhR activities (Jin et al., 2012). In
addition, although novel AhR-interacting drugs are not
yet approved, AhR-activating nutraceuticals, such as
Reference
No
No
No
Fritz et al., 2009; Zhang
et al., 2012
Prud’homme et al., 2010
DiNatale et al., 2012
Jin et al., 2012
Hauben et al., 2008;
Lawrence et al., 2008;
Baba et al., 2012
Loaiza-Pérez et al., 2004;
Callero et al., 2012
Yeste et al., 2012
Monteleone et al., 2011
Opitz et al., 2011
Shin et al., 2013
Boitano et al., 2010
van den Bogaard et al.,
2013
I3C, resveratrol, and 3,39-diindolylmethane, are being
marketed.
VII. Conclusions
Organisms must sense and respond to changes in the
environment in a meaningful way. The AhR is a protein
capable of sensing the (bio)chemical and physical environment. Together with its few high-affinity physiologic
ligands, such as FICZ and ICZ, it serves functions in cell
proliferation, differentiation and cell functions. The signaling system can be influenced by low-affinity chemicals and
even physical stressors such as oxidative stress, which
interfere with turnover of the “true” endogenous ligands. In
addition, xenobiotic high-affinity ligands can disrupt the
system, often to an extent that toxicity ensues, by
mimicking or competing with endogenous high-affinity
ligands. Barrier organs come in contact with many
exogenous chemicals, including human-made pollutants,
and chemicals characteristic for bacteria and fungi.
Barrier organs are characterized by high cell turnover
and express the AhR at high amounts in both their
structural and immune cells; indeed, barrier organs have
important immune functions. The AhR was demonstrated to have many functions in immune cells and
other cells; notably, AhR functions are very cell specific
and diverse. The high sensitivity and specificity of AhR
signaling are not fully understood. However, available
data, in animal models, animal and human cell lines
and organotypic cultures, as well as human epidemiology and human studies, suggest high potential for both
preventive and therapeutic intervention. More research
is needed to understand the full complexity of AhR
biology to avoid risks and master the opportunities of
therapy and prevention.
Aryl Hydrocarbon Receptor in Immunology and Toxicology
Acknowledgments
The authors thank Stephen Safe, Paige B. Lawrence, Heike Weighardt,
Bettina Jux, Thomas Haarmann-Stemmann, Jean Krutmann, and Ulf
Rannug for critical reading of the manuscript and helpful comments.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Esser,
Rannug.
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