Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD.
Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands. e.vandenbogaard@derma.umcn.nl
Ellen H
EH
van den Bogaard
Judith G M
JG
Bergboer
Mieke
M
Vonk-Bergers
Ivonne M J J
IM
van Vlijmen-Willems
Stanleyson V
SV
Hato
Pieter G M
PG
van der Valk
Jens Michael
JM
Schröder
Irma
I
Joosten
Patrick L J M
PL
Zeeuwen
Joost
J
Schalkwijk
D000287:Administration, Topical; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003033:Coal Tar / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D003033:Coal Tar