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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78 Citations (Scopus)


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.

Original languageEnglish
Article numbere2931
JournalCell Death and Disease
Issue number7
Publication statusPublished - Jul 2017

All Science Journal Classification (ASJC) codes

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


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