Revival of AHR Agonist for the Treatment of Atopic Dermatitis: Tapinarof
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Revival of AHR Agonist for the Treatment of Atopic Dermatitis: Tapinarof Masutaka Furue, MD, PhD1,2,3,* Takeshi Nakahara, MD, PhD1,3 Address 1 Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan 2 Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 31-1, Higashiku, Fukuoka, 812-8582, Japan *,3 Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan Email: [email protected]
* Springer Nature Switzerland AG 2020
Keywords Aryl hydrocarbon receptor (AHR) I Nuclear factor erythroid 2–related factor-2 (NRF2) I Atopic dermatitis I Tapinarof - Signal transducer and activator of transcription 6 (STAT6) I Filaggrin I Reactive oxygen species
Abstract Purpose of review The aryl hydrocarbon receptor (AHR) system is a sensitive sensor for small-molecule, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. Once activated, the AHR signal strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. Recent findings Coal tar and glyteer are crude mixtures of compounds that have been used for inflammatory skin diseases such as type 2 cytokine-dominant atopic dermatitis (AD). Both of them are antioxidative AHR ligands and simultaneously activate the nuclear factor erythroid 2–related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. Type 2 cytokines activate signal transducer and activator of transcription 6 (STAT6) and inhibit filaggrin expression. Coal tar and glyteer inhibit this type 2 cytokine-mediated STAT6 activation by decreasing the type 2 cytokine-induced oxidative stress. However, patients hesitate to use them on a daily basis because of their bad smell and black color. A single compound, tapinarof, is an antioxidative AHR agonist and also activates the NRF2 system. Recent clinical trials have revealed that topical tapinarof is efficacious for the treatment of AD. Its adverse events, including headache and folliculitis, are mild and tolerable. Summary Topical tapinarof may be a valuable substitute for coal tar and glyteer. Further clinical trials of its use, including for pediatric AD, are warranted.
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Introduction Atopic dermatitis (AD) is a common and heterogeneous eczematous skin disorder characterized by T helper type 2 (Th2)–deviated skin inflammation, barrier disruption, and chronic pruritus [1–3]. Frequent relapse with intense pruritus reduces the quality of life and decreases treatment satisfaction of the afflicted patients [4–8]. Skin barrier dysfunction is associated with the reduced production of terminal differentiation molecules such as filaggrin [9, 10••]. Abnormal skin barrier integrity also causes increased colonization of microbes such as Staphylococc
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