Abstract
Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
MeSH terms
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Adjuvants, Immunologic / pharmacology
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Aminoquinolines / pharmacology
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Animals
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Aryl Hydrocarbon Hydroxylases / biosynthesis
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Azo Compounds / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / agonists
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / immunology*
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Carbazoles / pharmacology
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Cytochrome P-450 CYP1A1 / biosynthesis
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Cytochrome P-450 CYP1B1
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Cytokines / pharmacology
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Environmental Exposure
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Humans
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Imiquimod
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Inflammation / immunology*
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Keratinocytes / immunology
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Mice
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Mice, Knockout
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Psoriasis / immunology*
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Psoriasis / pathology
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Pyrazoles / pharmacology
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Receptors, Aryl Hydrocarbon / agonists
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Receptors, Aryl Hydrocarbon / genetics
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Receptors, Aryl Hydrocarbon / immunology*
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Signal Transduction / immunology
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Skin / immunology
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Skin / metabolism
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Transcription Factors / biosynthesis
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Up-Regulation
Substances
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2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
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6-formylindolo(3,2-b)carbazole
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Adjuvants, Immunologic
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Ahr protein, mouse
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Aminoquinolines
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Azo Compounds
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Basic Helix-Loop-Helix Transcription Factors
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Carbazoles
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Cytokines
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JunB protein, mouse
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Pyrazoles
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Receptors, Aryl Hydrocarbon
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Transcription Factors
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Aryl Hydrocarbon Hydroxylases
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CYP1B1 protein, human
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Cyp1b1 protein, mouse
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1B1
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Imiquimod
Associated data
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GEO/GSE47607
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GEO/GSE47944