title: Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation.
abstract: Stimulation of the aryl hydrocarbon receptor (AHR) by xenobiotics is known to affect epidermal differentiation and skin barrier formation. The physiological role of endogenous AHR signaling in keratinocyte differentiation is not known. We used murine and human skin models to address the hypothesis that AHR activation is required for normal keratinocyte differentiation. Using transcriptome analysis of Ahr(-/-) and Ahr(+/+) murine keratinocytes, we found significant enrichment of differentially expressed genes linked to epidermal differentiation. Primary Ahr(-/-) keratinocytes showed a significant reduction in terminal differentiation gene and protein expression, similar to Ahr(+/+) keratinocytes treated with AHR antagonists GNF351 and CH223191, or the selective AHR modulator (SAhRM) SGA360. In vitro keratinocyte differentiation led to increased AHR levels and subsequent nuclear translocation, followed by induced CYP1A1 gene expression. Monolayer cultured primary human keratinocytes treated with AHR antagonists also showed an impaired terminal differentiation program. Inactivation of AHR activity during human skin equivalent development severely impaired epidermal stratification, terminal differentiation protein expression, and stratum corneum formation. As disturbed epidermal differentiation is a main feature of many skin diseases, pharmacological agents targeting AHR signaling or future identification of endogenous keratinocyte-derived AHR ligands should be considered as potential new drugs in dermatology.
authors.affiliation: Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Ellen H
authors.initials: EH
authors.lastname: van den Bogaard
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Carlisle, PA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Podolsky
authors.affiliation: Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Jos P
authors.initials: JP
authors.lastname: Smits
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Carlisle, PA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Carlisle, PA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: John
authors.affiliation: Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA, USA.
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA, USA.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA, USA.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Carlisle, PA, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Carlisle, PA, USA. Electronic address: abg11@psu.edu.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D000498:Allyl Compounds; D001391:Azo Compounds; D007191:Indazoles; D007211:Indoles; C560625:N-(2-(3H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methyl-3-pyridyl)purin-6-amine; D011687:Purines; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; C551534:SGA 360