title: Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.
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.
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: João H
authors.initials: JH
authors.lastname: Duarte
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Ahlfors
authors.affiliation: Division of Systems Biology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Nick D L
authors.initials: ND
authors.lastname: Owens
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: St. John's Institute of Dermatology, King's College London and NIHR Biomedical Research Centre, London SE1 9RT, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.affiliation: St. John's Institute of Dermatology, King's College London and NIHR Biomedical Research Centre, London SE1 9RT, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Tosi
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.affiliation: St. John's Institute of Dermatology, King's College London and NIHR Biomedical Research Centre, London SE1 9RT, UK.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.affiliation: Psoriasis Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
authors.affiliation: Division of Systems Biology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gilchrist
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Electronic address: bstocki@nimr.mrc.ac.uk.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Stockinger
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001391:Azo Compounds / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D002227:Carbazoles / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1; D016207:Cytokines / Q000494:pharmacology; D004781:Environmental Exposure; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D001189:Aryl Hydrocarbon Hydroxylases; D001391:Azo Compounds; D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D016207:Cytokines; D000077271:Imiquimod; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; C111855:6-formylindolo(3,2-b)carbazole; C484722:Ahr protein, mouse; C584097:JunB protein, mouse; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse