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 6

Model of the molecular mechanism of coal tar therapy in AD.

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Model of the molecular mechanism of coal tar therapy in AD. Th2 cytokine...
Th2 cytokines IL-4 and IL-13 activate the STAT6 signaling cascade, leading to downregulated expression of epidermal differentiation proteins, induction of the eosinophilic chemoattractant CCL26, and histopathological features such as spongiosis and apoptosis. Under normal conditions, PTPN1 dephosphorylates STAT6, resulting in a regulatory feedback loop. However, oxidative stress caused by Th2 cytokines inactivates PTPN1, leading to sustained STAT6 signaling. Coal tar–mediated activation of the AHR signaling pathway leads to enhanced epidermal differentiation and possible improvement of epidermal barrier function, thereby attenuating allergen exposure and reducing inflammatory cues. Importantly, coal tar activates the AHR/NRF2 signaling pathway, enabling detoxification of reactive oxygen species. This may prevent the oxidative inactivation of PTPN1 and lead to decreased STAT6 signaling, normalization of skin barrier protein expression, and downregulation of CCL26 expression.