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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Research Article

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 4

Coal tar attenuates Th2 cytokine–induced AD hallmarks.

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Coal tar attenuates Th2 cytokine–induced AD hallmarks. (A) H&E stain...
(A) H&E staining of skin equivalents stimulated with Th2 cytokines for 3 days, or treated with coal tar thereafter (Th2 → coal tar), or simultaneously stimulated with Th2 cytokines and coal tar (Th2 + coal tar). Closed arrowheads indicate spongiosis. Images are representative of 3 keratinocyte donors. The experiment was replicated twice. Scale bar: 100 μM. (B) TUNEL assay on matching skin equivalents as depicted in A, showing apoptotic cells indicated by open arrowheads. Scale bar: 100 μM. (C) FAS mRNA expression levels in skin equivalents after Th2 cytokine stimulation and coal tar treatment. Expression levels are relative to untreated (control) keratinocytes. Bars indicate mean ± SEM (n = 3). (D) mRNA expression levels of epidermal differentiation genes after Th2 cytokine stimulation and coal tar treatment. Expression levels are relative to untreated (control) keratinocytes. Bars indicate mean ± SEM (n = 3). *P < 0.05 and **P < 0.01. (E) Immunohistochemical staining of loricrin and involucrin in skin equivalents stimulated with Th2 cytokines for 3 days, or treated with coal tar thereafter (Th2 → coal tar). Images are representative of 3 keratinocyte donors. The experiment was replicated twice. Scale bar: 100 μM. (F) Loricrin, involucrin, and filaggrin Western blotting of skin equivalents are depicted in E. (G) CCL26 mRNA expression levels after Th2 cytokine stimulation and coal tar treatment by qPCR analysis. Expression levels are relative to untreated (control) keratinocytes. Bars indicate mean ± SEM (n = 3). ***P < 0.001.