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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.
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 (
). 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 (
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.
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 (
). 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 (
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 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 (
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 (
). 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 (
). AHR activation is also thought to propagate tumor formation because it may lead to an induction of extracellular matrix–degrading (ECM) matrix metalloproteases (
). 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 (
). 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 (
), 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 (
), 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 (
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.
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 (
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 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 (
). 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 (
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 (
). 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 (
) 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 (
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.
), 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 (
Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide.
). 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.
Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in keratinocytes.
Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide.
Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo.
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.
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.
The Tryptophan-derived endogenous aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes.
Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential activation states suggest distinct functions.
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.
The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction.
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