Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to structurally diverse synthetic and naturally occurring chemicals including dioxins, flavonoids, tryptophan photoproducts, and Malassezia metabolites. Upon binding to its ligands, cytoplasmic AhR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological and toxicological effects by inducing the transcription of various AhR-responsive genes. AhR ligation controls oxidation/antioxidation, epidermal barrier function, photo-induced response, melanogenesis, and innate immunity. This review summarizes recent advances in the understanding of the regulatory mechanisms of skin homeostasis mediated by the AhR/ARNT system.

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.

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