Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis
Ellen H. van den Bogaard, … , Patrick L.J.M. Zeeuwen, Joost Schalkwijk
Ellen H. van den Bogaard, … , Patrick L.J.M. Zeeuwen, Joost Schalkwijk
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):917-927. https://doi.org/10.1172/JCI65642.
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Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis

Abstract

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.

Authors

Ellen H. van den Bogaard, Judith G.M. Bergboer, Mieke Vonk-Bergers, Ivonne M.J.J. van Vlijmen-Willems, Stanleyson V. Hato, Pieter G.M. van der Valk, Jens Michael Schröder, Irma Joosten, Patrick L.J.M. Zeeuwen, Joost Schalkwijk

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Figure 1

Coal tar induces epidermal differentiation via AHR signaling.

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Coal tar induces epidermal differentiation via AHR signaling. (A) AHR st...
(A) AHR staining of coal tar–treated or untreated keratinocytes. Nuclei were counterstained using DAPI. Scale bar: 100 μM. (B) Semiquantitative analysis of nuclear and cytoplasmic fluorescence intensity (FI) measured by ImageJ software. *P < 0.05, **P < 0.01, and ***P < 0.001, relative to untreated keratinocytes. Bars indicate mean ± SEM (n = 3). (C) CYP450 mRNA expression levels after 48 hours of stimulation with TCDD or a coal tar concentration series. Expression levels are relative to untreated (control) keratinocytes. *P < 0.05 and **P < 0.001. Bars indicate mean ± SEM (n = 3). (D) mRNA expression levels of epidermal differentiation genes after 48 hours of stimulation with TCDD or a coal tar concentration series. Expression levels are relative to untreated (control) keratinocytes. Bars indicate mean ± SEM (n = 3). (E) Filaggrin and hornerin staining of 2% coal tar–treated or untreated keratinocytes. Nuclei were counterstained using DAPI. Scale bar: 100 μM. (F) Western blot analysis of filaggrin protein in lysates of coal tar–treated and untreated keratinocytes from 2 keratinocyte donors. (G) Filaggrin staining of 2% coal tar–treated or untreated keratinocytes. Nuclei were counterstained using hematoxylin. Scale bar: 100 μM. (H) AHR and CYP1A1, and (I) FLG and HRNR mRNA expression levels after siRNA-mediated AHR knockdown and subsequent 2% coal tar stimulation. Expression levels are relative to mock-treated, coal tar–stimulated keratinocytes. Bars indicate mean ± SEM (n = 3).