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The Janus-Faced Role of Aryl Hydrocarbon Receptor Signaling in the Skin: Consequences for Prevention and Treatment of Skin Disorders

      The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor expressed in all skin cell types, which is critically involved in the pathogenesis of a variety of skin diseases and thus represents a potential therapeutic target. Recent studies indicate that blocking AHR activation is desirable in some skin conditions, whereas the opposite, i.e., stimulation of AHR activation, is beneficial in another group of skin disorders. We here propose a model based on qualitative differences in canonical versus non-canonical AHR signaling to reconcile these seemingly contradictory observations.
      AD
      atopic dermatitis
      AHR
      aryl hydrocarbon receptor
      ARNT
      aryl hydrocarbon receptor nuclear translocator
      BDDI
      E/Z-2-benzylidene-5,6-dimethoxy-3,3-dimethylindan-1-one
      ECM
      extracellular matrix
      FICZ
      6-formylindolo[3,2b]carbazole
      NCI
      non-canonical inflammatory AHR signaling
      Nrf2
      nuclear factor erythroid 2-related factor 2
      PAH
      polycyclic aromatic hydrocarbons
      ROS
      reactive oxygen species
      STAT
      signal transducer and activator of transcription
      Sensing and warding off environmental insults is a crucial function of the skin. In this context, the aryl hydrocarbon receptor (AHR) has recently been discovered as an important player in skin integrity and skin immunity. AHR is an evolutionarily old, ligand-activated transcription factor, which is expressed highly in all skin cell types, and regulates many genes important for basic skin functions (
      • Esser C.
      • Bargen I.
      • Weighardt H.
      • et al.
      Functions of the aryl hydrocarbon receptor in the skin.
      ;
      • Furue M.
      • Takahara M.
      • Nakahara T.
      • et al.
      Role of AhR/ARNT system in skin homeostasis.
      ). On the downside, AHR signaling was found to be critically involved in the pathogenesis of several cutaneous diseases. Therefore, AHR is increasingly considered an attractive therapeutic target.
      When inactive, AHR is trapped in a cytosolic multiprotein complex. Ligand binding dissolves the complex and AHR can translocate into the nucleus, where it dimerizes with a partner molecule to become a functioning transcription factor at promoters with suitable response elements. The first AHR dimerization partner discovered was the AHR nuclear translocator (ARNT). AHR:ARNT signaling is known as canonical signaling, but it has become clear that activated AHR can interact in a non-canonical manner with other signaling cascades, including pro-inflammatory and immune modulatory molecules, such as the EGFR and downstream mitogen–activated protein kinases (
      • Park S.
      • Matsumura F.
      Characterization of anti-apoptotic action of TCDD as a defensive cellular stress response reaction against the cell damaging action of ultra-violet irradiation in an immortalized normal human mammary epithelial cell line, MCF10A.
      ;
      • Fritsche E.
      • Schafer C.
      • Calles C.
      • et al.
      Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
      ), NF-κB (
      • Tian Y.
      • Ke S.
      • Denison M.S.
      • et al.
      Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity.
      ;
      • Vogel C.F.
      • Sciullo E.
      • Li W.
      • et al.
      RelB, a new partner of aryl hydrocarbon receptor-mediated transcription.
      ), signal transducer and activator of transcription (STATs;
      • Kimura A.
      • Naka T.
      • Nohara K.
      • et al.
      Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.
      ;
      • Kimura A.
      • Naka T.
      • Nakahama T.
      • et al.
      Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.
      ), peroxisome proliferator–activated receptors (
      • Borland M.G.
      • Krishnan P.
      • Lee C.
      • et al.
      Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in keratinocytes.
      ), and others. This gives AHR a strong cell-specific spin, whose regulation is poorly understood. We propose here that the outcome of AHR activation markedly differs in healthy versus inflamed skin, which needs to be considered in AHR-targeting therapies.
      Ligands of AHR are abundant in and on the skin. They include chemicals such as polycyclic aromatic hydrocarbons (PAH) and indole derivatives produced by skin-residing microorganisms (
      • Esser C.
      • Rannug A.
      The aryl hydrocarbon receptor in barrier organ physiology, immunology, toxicology.
      )––for instance, by yeasts of the Malassezia strain (
      • Magiatis P.
      • Pappas P.
      • Gaitanis G.
      • et al.
      Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin.
      ;
      • Mexia N.
      • Gaitanis G.
      • Velegraki A.
      • et al.
      Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast.
      ). In the absence of exogenous ligands, AHR signaling in healthy skin is maintained and regulated via the generation of endogenous AHR ligands to assure skin homeostasis. Specifically, UV-B rays are absorbed by free tryptophan in the cytosol of epidermal cells, which results in the formation of the photoproduct 6-formylindolo[3,2b]carbazole (FICZ), a high-affinity ligand for the AHR (
      • Wei Y.D.
      • Rannug U.
      • Rannug A.
      UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan.
      ;
      • Fritsche E.
      • Schafer C.
      • Calles C.
      • et al.
      Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
      ;
      • Tigges J.
      • Haarmann-Stemmann T.
      • Vogel C.F.
      • et al.
      The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction.
      ). Interestingly, this tryptophan photoproduct was recently identified as a potent photosensitizer for UV-A radiation (
      • Park S.L.
      • Justiniano R.
      • Williams J.D.
      • et al.
      The Tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes.
      ). Whether and to which extent the photosensitizing property of FICZ influences (patho)physiological processes in UV-exposed skin remains to be elucidated. Besides FICZ, which is probably ubiquitously distributed in skin cells (
      • Wincent E.
      • Bengtsson J.
      • Mohammadi B.A.
      • et al.
      Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.
      ), AHR activity may be maintained by kynurenines (
      • Mezrich J.D.
      • Fechner J.H.
      • Zhang X.
      • et al.
      An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.
      ), which are generated by indoleamine-2,3-dioxygenase and tryptophan-2,3-dioxygenase during tryptophan catabolism (
      • Platten M.
      • Wick W.
      • Van den Eynde B.J.
      Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.
      ). Notably, both enzymes are expressed in the skin, particularly in various skin-residing immune cells (
      • Santegoets S.J.A.M.
      • Gibbs S.
      • Kroeze K.
      • et al.
      Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential activation states suggest distinct functions.
      ).
      In the last decade, several studies have provided ample evidence that AHR is involved in the pathogenesis of various skin diseases and generated excitement that targeting of AHR may be a novel and a promising preventive or therapeutic strategy. The current data, however, are contradictory. One group of studies indicates that blocking AHR activity is suitable to prevent or treat certain skin diseases (especially skin cancer), whereas the opposite seems to be true for other skin disorders (e.g., psoriasis). Accordingly, activation of AHR in healthy skin by PAH and UV-B radiation induces cellular events, which may foster the generation of reactive metabolites and the accumulation of damaged macromolecules and thereby initiate extrinsic aging processes and carcinogenesis (
      • Esser C.
      • Bargen I.
      • Weighardt H.
      • et al.
      Functions of the aryl hydrocarbon receptor in the skin.
      ;
      • Esser C.
      • Rannug A.
      The aryl hydrocarbon receptor in barrier organ physiology, immunology, toxicology.
      ). AHR is a negative regulator of apopotosis in UV-B-damaged keratinocytes, indicating its involvement in initiation of skin cancer (
      • Frauenstein K.
      • Sydlik U.
      • Tigges J.
      • et al.
      Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1.
      ). In addition, enhanced production of cytochrome P450 1 enzymes may lead to the generation of reactive oxygen species (ROS) and mutagenic PAH metabolites, which may damage proteins and DNA (
      • Ioannides C.
      • Lewis D.F.
      Cytochromes P450 in the bioactivation of chemicals.
      ). AHR activation is also thought to propagate tumor formation because it may lead to an induction of extracellular matrix–degrading (ECM) matrix metalloproteases (
      • Murphy K.A.
      • Villano C.M.
      • Dorn R.
      • et al.
      Interaction between the aryl hydrocarbon receptor and retinoic acid pathways increases matrix metalloproteinase-1 expression in keratinocytes.
      ;
      • Ono Y.
      • Torii K.
      • Fritsche E.
      • et al.
      Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression.
      ), as well as pro-inflammatory and anti-apoptotic mediators, such as cyclooxygenase-2 and IL-1β (
      • Sutter T.
      • Guzman K.
      • Dold K.
      • et al.
      Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta.
      ;
      • Fritsche E.
      • Schafer C.
      • Calles C.
      • et al.
      Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
      ). Importantly, AHR knockdown reduces photocarcinogenesis in a mouse model by 50% (
      • Haarmann-Stemmann T.
      • Frauenstein K.
      • Tigges J.
      • et al.
      The aryl hydrocarbon receptor (AHR) is a new target for prevention and treatment of cutaneous squamous cell carcinomas.
      ). Thus, inhibition of cutaneous AHR activity, especially in times of high exposure to these environmental factors, most probably protects skin integrity.
      This is in striking contrast to the effect of AHR activation in situations of chronic inflammatory skin diseases including atopic dermatitis and psoriasis. Topical treatment of lesional skin with PAH-containing coal tar is known for a long time to be beneficial in both skin diseases. In atopic dermatitis (AD), AHR activation restores filaggrin expression and exerts an anti-inflammatory activity by preventing IL-4- and IL-13-induced skin inflammation. Coal tar–dependent induction of nuclear factor erythroid 2-related factor 2 (Nrf2) activity and accompanying anti-oxidant genes neutralizes cytokine-activated STAT-6 and attenuates downstream pro-inflammatory processes (
      • van den Bogaard E.H.
      • Bergboer J.G.
      • Vonk-Bergers M.
      • et al.
      Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
      ). Topical application of AHR ligands also dampens skin inflammation in psoriasis (
      • Di Meglio P.
      • Duarte J.H.
      • Ahlfors H.
      • et al.
      Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
      ). Stimulation of human lesional psoriatic skin with FICZ decreased transcriptional expression of genes that are expressed at elevated levels in psoriatic skin, whereas treatment with an AHR inhibitor had the opposite effect. In addition, in the imiquimod mouse model of psoriasis (
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.A.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ), skin inflammation was stronger in AHR-KO mice compared with their wild-type littermates and activation of AHR by injection of FICZ before imiquimod treatment reduced skin inflammation (
      • Di Meglio P.
      • Duarte J.H.
      • Ahlfors H.
      • et al.
      Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
      ). Also, it was suggested that a ROS-mediated disturbance of AHR signaling contributes to the development of vitiligo (
      • Schallreuter K.U.
      • Salem M.A.
      • Gibbons N.C.
      • et al.
      Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H2O2/ONOO(-)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling.
      ). Accordingly, AHR drives skin pigmentation (
      • Luecke S.
      • Backlund M.
      • Jux B.
      • et al.
      The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis.
      ;
      • Jux B.
      • Kadow S.
      • Luecke S.
      • et al.
      The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning.
      ;
      • Nakamura M.
      • Ueda Y.
      • Hayashi M.
      • et al.
      Tobacco smoke-induced skin pigmentation is mediated by the aryl hydrocarbon receptor.
      ), and, loss of AHR signaling may partially explain increased oxidative stress levels in vitiligo skin, as it can lead to the impaired activation of the Nrf2 system (
      • Miao W.
      • Hu L.
      • Scrivens P.J.
      • et al.
      Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.
      ;
      • Tsuji G.
      • Takahara M.
      • Uchi H.
      • et al.
      Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect.
      ) and thereby reduce expression of ROS-scavenging enzymes in vitiligo melanocytes (
      • Jian Z.
      • Li K.
      • Song P.
      • et al.
      Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo.
      ). Similar to effective coal tar treatment in AD and psoriasis, the two most widely used therapies for vitiligo, Psoralen/Khellin plus UV-A (PUVA/KUVA) photochemotherapy and exposure to narrow-band UV-B radiation (
      • Ortonne J.P.
      • MacDonald D.M.
      • Micoud A.
      • et al.
      PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultrastructural study.
      ;
      • Carlie G.
      • Ntusi N.B.
      • Hulley P.A.
      • et al.
      KUVA (khellin plus ultraviolet A) stimulates proliferation and melanogenesis in normal human melanocytes and melanoma cells in vitro.
      ;
      • Pacifico A.
      • Leone G.
      Photo(chemo)therapy for vitiligo.
      ), can activate AHR signaling (
      • Baumgart A.
      • Schmidt M.
      • Schmitz H.J.
      • et al.
      Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes.
      ;
      • Fritsche E.
      • Schafer C.
      • Calles C.
      • et al.
      Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
      ;
      • Vrzal R.
      • Frauenstein K.
      • Proksch P.
      • et al.
      Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.
      ) and may thereby contribute to repigmentation.
      Thus, it appears that alteration of AHR signaling in the skin may have detrimental or beneficial effects depending on the disease, the participating cells, and whether or not the immune system is active concurrently on the systemic or the local level. In particular, inflammatory situations may change AHR signaling, possibly shifting it toward non-canonical pro-inflammatory signaling. Accordingly, AHR inhibition most likely protects human skin against detrimental consequences of AHR over-activation caused by environmental toxicants, such as air pollution and tobacco smoke–associated PAHs or UV-B radiation, and thereby reduces the risk of developing skin cancer and skin aging. In contrast, AHR stimulation appears to be beneficial for the treatment of AD, psoriasis, and potentially vitiligo, where the disease has unbalanced AHR activity. In order to explain this Janus-faced role of AHR in the skin, we here propose that AHR signaling is qualitatively different in normal healthy versus chronically inflamed skin (Figure 1).
      Figure thumbnail gr1
      Figure 1Graphic scheme of the hypothesis presented in this paper. In healthy skin (middle), the aryl hydrocarbon receptor (AHR) is constitutively active, and canonical and non-canonical-mediated signaling processes are tightly balanced. In xenobiotic AHR ligand–exposed skin (left), canonical AHR:aryl hydrocarbon receptor nuclear translocator (ARNT) signaling may become dominant and lead to a set of adverse effects as indicated in the figure. In inflamed skin (right), high levels of non-canonical AHR-partner molecules are expressed, unbalancing AHR signaling toward non-canonical inflammatory (NCI) AHR:NCI target genes, resulting in different adverse effects. Balance can be restored by AHR antagonists or agonist, respectively. Possible non-canonical inflammatory AHR-partner molecules, such as NF-κB, have been described in the literature; for details see text. The dendritic cell shown in the epidermal compartment should symbolize the variety of skin-resident immune cells.
      In healthy skin, AHR signaling driven by endogenous ligands, such as FICZ, contributes to keratinocyte differentiation, skin barrier function, and skin pigmentation (
      • Wei Y.D.
      • Bergander L.
      • Rannug U.
      • et al.
      Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole.
      ;
      • Wincent E.
      • Amini N.
      • Luecke S.
      • et al.
      The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.
      ;
      • van den Bogaard E.
      • Podolsky M.
      • Smits J.
      • et al.
      Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation.
      ). Exposure to environmental toxicants—which often are not or only slowly degraded––may persistently activate the AHR and thereby disturb this fine-tuned system, leading to the generation of reactive phase-I metabolites, the generation of ROS, and dysregulation of proteins involved in cell division, differentiation, migration, and apoptosis. Depending on the capacity of respective downstream control or scavenging mechanisms, this may lead to metabolic activation of pre-carcinogens, ECM degradation, inflammation, and anti-apoptosis and thus ultimately to skin cancer development and extrinsic skin aging. According to our model (Figure 1), a transient AHR inhibition is thus clearly desirable, when environmental pollutants or UV exposure threatens skin integrity. To this end, we have developed a novel transiently acting AHR antagonist E/Z-2-benzylidene-5,6-dimethoxy-3,3-dimethylindan-1-one (BDDI), which is approved for topical application to human skin as a cosmetic ingredient, and shown that BDDI treatment of defined skin areas blocks AHR-dependent signaling (
      • Tigges J.
      • Haarmann-Stemmann T.
      • Vogel C.F.
      • et al.
      The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction.
      ).
      The scenario described above, however, is in contrast to the one present in chronically inflamed skin, such as AD, psoriasis, and possibly vitiligo. In chronically inflamed skin, AHR expression appears to be aberrantly induced (
      • Kim H.O.
      • Kim J.H.
      • Chung B.Y.
      • et al.
      Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases.
      ), probably via pro-inflammatory transcription factors, such as NF-κB and STAT-3 (
      • Stobbe-Maicherski N.
      • Wolff S.
      • Wolff C.
      • et al.
      The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells.
      ;
      • Vogel C.F.
      • Khan E.M.
      • Leung P.S.
      • et al.
      Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-kappaB.
      ). This may lead to silencing or outcompeting of canonical AHR signaling and consequently to alterations of the gene expression profile in the skin. At the same time, the chronic inflammatory state might enforce non-canonical AHR signaling pathways (e.g., by AHR binding to NF-κB, c-maf, and STATs), which would change the production of cytokines or growth factors in the skin (
      • Tian Y.
      • Ke S.
      • Denison M.S.
      • et al.
      Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity.
      ;
      • Vogel C.F.
      • Sciullo E.
      • Li W.
      • et al.
      RelB, a new partner of aryl hydrocarbon receptor-mediated transcription.
      ;
      • Hollingshead B.D.
      • Beischlag T.V.
      • Dinatale B.C.
      • et al.
      Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells.
      ;
      • Kimura A.
      • Naka T.
      • Nohara K.
      • et al.
      Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.
      ,
      • Kimura A.
      • Naka T.
      • Nakahama T.
      • et al.
      Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.
      ;
      • Apetoh L.
      • Quintana F.J.
      • Pot C.
      • et al.
      The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27.
      ) and contribute to disease development and/or persistence.
      Administration of potent AHR agonists may overcome this repressive mechanism and restore canonical AHR signaling and thus the balance between canonical and non-canonical pathways. Thus, for prevention of skin cancer and skin aging, the preferred strategy should be to prevent or at least dampen AHR over-activation resulting from environmental insults. In contrast, in chronic inflammatory skin diseases, where AHR signaling is unbalanced, reconstitution of functional AHR signaling is desirable, with the goal to induce AHR/ARNT-regulated genes and the subsequent promotion of keratinocyte differentiation and proliferation, skin pigmentation, and anti-oxidant defenses. Given the therapeutic efficacy of PAH-containing coal tar in AD and psoriasis and of FICZ-generating photo(chemo)therapeutic modalities in vitiligo, we believe that stimulation of AHR with appropriate ligands can in fact “do the job”. According to our model, strategies to reduce oxidative stress, which have been advocated for the treatment of vitiligo and AD (
      • Schallreuter K.U.
      • Salem M.A.
      • Holtz S.
      • et al.
      Basic evidence for epidermal H2O2/ONOO(-)-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS.
      ;
      • Sivaranjani N.
      • Rao S.V.
      • Rajeev G.
      Role of reactive oxygen species and antioxidants in atopic dermatitis.
      ), might also help reconstitute canonical AHR signaling.
      The precise reason why canonical AHR signaling is compromised under inflammatory conditions is unclear but may for instance involve the generation of nitric oxide (
      • Stadler J.
      • Trockfeld J.
      • Schmalix W.A.
      • et al.
      Inhibition of cytochromes P4501A by nitric oxide.
      ;
      • Gharavi N.
      • El-Kadi A.O.
      Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide.
      ) or chromatin remodeling processes at target gene promoters (
      • Ke S.
      • Rabson A.B.
      • Germino J.F.
      • et al.
      Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide.
      ). Also, EGFR-signaling-dependent AHR repression could be important (
      • Sutter C.H.
      • Yin H.
      • Li Y.
      • et al.
      EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes.
      ). In addition, expression levels and relative abundance of the involved molecules might have a role. Therefore, we also think that more information on the non-canonical pathways is needed to fully explore the potential of AHR as a therapeutic target.

      Conflict of Interest

      The authors state no conflict of interest.

      ACKNOWLEDGMENTS

      We thank Bernhard Homey for critically reading the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft, grants ES103/5-1 and ES103/6-1 (to CE), and the Wilhelm-Sander-Foundation (to TH-S).

      REFERENCES

        • Apetoh L.
        • Quintana F.J.
        • Pot C.
        • et al.
        The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27.
        Nat Immunol. 2010; 11: 854-861
        • Baumgart A.
        • Schmidt M.
        • Schmitz H.J.
        • et al.
        Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes.
        Biochem Pharmacol. 2005; 69: 657-667
        • Borland M.G.
        • Krishnan P.
        • Lee C.
        • et al.
        Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in keratinocytes.
        Carcinogenesis. 2014; 35: 1602-1612
        • Carlie G.
        • Ntusi N.B.
        • Hulley P.A.
        • et al.
        KUVA (khellin plus ultraviolet A) stimulates proliferation and melanogenesis in normal human melanocytes and melanoma cells in vitro.
        Br J Dermatol. 2003; 149: 707-717
        • Di Meglio P.
        • Duarte J.H.
        • Ahlfors H.
        • et al.
        Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
        Immunity. 2014; 40: 989-1001
        • Esser C.
        • Rannug A.
        The aryl hydrocarbon receptor in barrier organ physiology, immunology, toxicology.
        Pharmacol Rev. 2015; 67: 1-21
        • Esser C.
        • Bargen I.
        • Weighardt H.
        • et al.
        Functions of the aryl hydrocarbon receptor in the skin.
        Semin Immunopathol. 2013; 35: 677-691
        • Frauenstein K.
        • Sydlik U.
        • Tigges J.
        • et al.
        Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1.
        Cell Death Differ. 2013; 20: 1425-1434
        • Fritsche E.
        • Schafer C.
        • Calles C.
        • et al.
        Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
        Proc Natl Acad Sci USA. 2007; 104: 8851-8856
        • Furue M.
        • Takahara M.
        • Nakahara T.
        • et al.
        Role of AhR/ARNT system in skin homeostasis.
        Arch Dermatol Res. 2014; 306: 769-779
        • Gharavi N.
        • El-Kadi A.O.
        Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide.
        J Pharm Sci. 2007; 96: 2795-2807
        • Haarmann-Stemmann T.
        • Frauenstein K.
        • Tigges J.
        • et al.
        The aryl hydrocarbon receptor (AHR) is a new target for prevention and treatment of cutaneous squamous cell carcinomas.
        J Investig Dermatol Symp Proc. 2014; 134: S28
        • Hollingshead B.D.
        • Beischlag T.V.
        • Dinatale B.C.
        • et al.
        Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells.
        Cancer Res. 2008; 68: 3609-3617
        • Ioannides C.
        • Lewis D.F.
        Cytochromes P450 in the bioactivation of chemicals.
        Curr Top Med Chem. 2004; 4: 1767-1788
        • Jian Z.
        • Li K.
        • Song P.
        • et al.
        Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo.
        J Investig Dermatol Symp Proc. 2014; 134: 2221-2230
        • Jux B.
        • Kadow S.
        • Luecke S.
        • et al.
        The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning.
        J Investig Dermatol Symp Proc. 2011; 131: 203-210
        • Ke S.
        • Rabson A.B.
        • Germino J.F.
        • et al.
        Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide.
        J Biol Chem. 2001; 276: 39638-39644
        • Kim H.O.
        • Kim J.H.
        • Chung B.Y.
        • et al.
        Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases.
        Exp Dermatol. 2014; 23: 278-281
        • Kimura A.
        • Naka T.
        • Nakahama T.
        • et al.
        Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.
        J Exp Med. 2009; 206: 2027-2035
        • Kimura A.
        • Naka T.
        • Nohara K.
        • et al.
        Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.
        Proc Natl Acad Sci USA. 2008; 105: 9721-9726
        • Luecke S.
        • Backlund M.
        • Jux B.
        • et al.
        The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis.
        Pigment Cell Melanoma Res. 2010; 23: 828-833
        • Magiatis P.
        • Pappas P.
        • Gaitanis G.
        • et al.
        Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin.
        J Investig Dermatol Symp Proc. 2013; 133: 2023-2030
        • Mexia N.
        • Gaitanis G.
        • Velegraki A.
        • et al.
        Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast.
        Arch Biochem Biophys. 2015; 571: 16-20
        • Mezrich J.D.
        • Fechner J.H.
        • Zhang X.
        • et al.
        An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.
        J Immunol. 2010; 185: 3190-3198
        • Miao W.
        • Hu L.
        • Scrivens P.J.
        • et al.
        Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.
        J Biol Chem. 2005; 280: 20340-20348
        • Murphy K.A.
        • Villano C.M.
        • Dorn R.
        • et al.
        Interaction between the aryl hydrocarbon receptor and retinoic acid pathways increases matrix metalloproteinase-1 expression in keratinocytes.
        J Biol Chem. 2004; 279: 25284-25293
        • Nakamura M.
        • Ueda Y.
        • Hayashi M.
        • et al.
        Tobacco smoke-induced skin pigmentation is mediated by the aryl hydrocarbon receptor.
        Exp Dermatol. 2013; 22: 556-558
        • Ono Y.
        • Torii K.
        • Fritsche E.
        • et al.
        Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression.
        Exp Dermatol. 2013; 22: 349-353
        • Ortonne J.P.
        • MacDonald D.M.
        • Micoud A.
        • et al.
        PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultrastructural study.
        Br J Dermatol. 1979; 101: 1-12
        • Pacifico A.
        • Leone G.
        Photo(chemo)therapy for vitiligo.
        Photodermatol Photoimmunol Photomed. 2011; 27: 261-277
        • Park S.
        • Matsumura F.
        Characterization of anti-apoptotic action of TCDD as a defensive cellular stress response reaction against the cell damaging action of ultra-violet irradiation in an immortalized normal human mammary epithelial cell line, MCF10A.
        Toxicology. 2006; 217: 139-146
        • Park S.L.
        • Justiniano R.
        • Williams J.D.
        • et al.
        The Tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes.
        J Investig Dermatol Symp Proc. 2015; 135: 1649-1658
        • Platten M.
        • Wick W.
        • Van den Eynde B.J.
        Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.
        Cancer Res. 2012; 72: 5435-5440
        • Santegoets S.J.A.M.
        • Gibbs S.
        • Kroeze K.
        • et al.
        Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential activation states suggest distinct functions.
        J Leuk Biol. 2008; 84: 143-151
        • Schallreuter K.U.
        • Salem M.A.
        • Gibbons N.C.
        • et al.
        Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H2O2/ONOO(-)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling.
        Faseb J. 2012; 26: 2471-2485
        • Schallreuter K.U.
        • Salem M.A.
        • Holtz S.
        • et al.
        Basic evidence for epidermal H2O2/ONOO(-)-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS.
        Faseb J. 2013; 27: 3113-3122
        • Sivaranjani N.
        • Rao S.V.
        • Rajeev G.
        Role of reactive oxygen species and antioxidants in atopic dermatitis.
        J Clin Diagn Res. 2013; 7: 2683-2685
        • Stadler J.
        • Trockfeld J.
        • Schmalix W.A.
        • et al.
        Inhibition of cytochromes P4501A by nitric oxide.
        Proc Natl Acad Sci USA. 1994; 91: 3559-3563
        • Stobbe-Maicherski N.
        • Wolff S.
        • Wolff C.
        • et al.
        The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells.
        Febs J. 2013; 280: 6681-6690
        • Sutter C.H.
        • Yin H.
        • Li Y.
        • et al.
        EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes.
        Proc Natl Acad Sci USA. 2009; 106: 4266-4271
        • Sutter T.
        • Guzman K.
        • Dold K.
        • et al.
        Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta.
        Science. 1991; 254: 415-418
        • Tian Y.
        • Ke S.
        • Denison M.S.
        • et al.
        Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity.
        J Biol Chem. 1999; 274: 510-515
        • Tigges J.
        • Haarmann-Stemmann T.
        • Vogel C.F.
        • et al.
        The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction.
        J Investig Dermatol Symp Proc. 2014; 134: 556-559
        • Tsuji G.
        • Takahara M.
        • Uchi H.
        • et al.
        Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect.
        J Investig Dermatol Symp Proc. 2012; 132: 59-68
        • van den Bogaard E.
        • Podolsky M.
        • Smits J.
        • et al.
        Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation.
        J Investig Dermatol Symp Proc. 2015; 135: 1320-1328
        • van den Bogaard E.H.
        • Bergboer J.G.
        • Vonk-Bergers M.
        • et al.
        Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
        J Clin Invest. 2013; 123: 917-927
        • van der Fits L.
        • Mourits S.
        • Voerman J.S.A.
        • et al.
        Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
        J Immunol. 2009; 182: 5836-5845
        • Vogel C.F.
        • Khan E.M.
        • Leung P.S.
        • et al.
        Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-kappaB.
        J Biol Chem. 2014; 289: 1866-1875
        • Vogel C.F.
        • Sciullo E.
        • Li W.
        • et al.
        RelB, a new partner of aryl hydrocarbon receptor-mediated transcription.
        Mol Endocrinol. 2007; 21: 2941-2955
        • Vrzal R.
        • Frauenstein K.
        • Proksch P.
        • et al.
        Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.
        PLoS One. 2013; 8: e74917
        • Wei Y.D.
        • Bergander L.
        • Rannug U.
        • et al.
        Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole.
        Arch Biochem Biophys. 2000; 383: 99-107
        • Wei Y.D.
        • Rannug U.
        • Rannug A.
        UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan.
        Chem Biol Interact. 1999; 118: 127-140
        • Wincent E.
        • Amini N.
        • Luecke S.
        • et al.
        The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.
        J Biol Chem. 2009; 284: 2690-2696
        • Wincent E.
        • Bengtsson J.
        • Mohammadi B.A.
        • et al.
        Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.
        Proc Natl Acad Sci USA. 2012; 109: 4479-4484