Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis

Gaku Tsuji, Akiko Hashimoto-Hachiya, Mari Kiyomatsu-Oda, Masaki Takemura, Fumitaka Ohno, Takamichi Ito, Saori Morino-Koga, Chikage Mitoma, Takeshi Nakahara, Hiroshi Uchi, Masutaka Furue

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Filaggrin (FLG) mutation is a well-confirmed genetic aberration in atopic dermatitis (AD). Genome-wide association studies on AD have revealed other susceptibility genes, for example, Ovo-like 1 (OVOL1). Nonetheless, the relation between FLG and OVOL1 is unclear. Because aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor), plays a role in FLG expression in keratinocytes, we hypothesized that AHR regulates FLG expression via OVOL1. To demonstrate this mechanism, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown normal human epidermal keratinocytes (NHEKs). Furthermore, we tested whether AHR activation by 6-formylindolo(3,2-b)carbazole (FICZ), an endogenous AHR ligand, or Glyteer, clinically used soybean tar, upregulates FLG and OVOL1 expression in NHEKs. We found that (1) OVOL1 regulates FLG expression; (2) AHR activation upregulates OVOL1; and (3) AHR activation upregulates FLG via OVOL1. Moreover, nuclear translocation of OVOL1 was less pronounced in AD skin compared with normal skin. IL-4-treated NHEKs, an in vitro AD skin model, also showed inhibition of the OVOL1 nuclear translocation, which was restored by FICZ and Glyteer. Thus, targeting the AHR-OVOL1-FLG axis may provide new therapeutics for AD.

元の言語英語
ページ(範囲)e2931
ジャーナルCell death & disease
8
発行部数7
DOI
出版物ステータス出版済み - 7 13 2017

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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