Abstract
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.
Highlights
Mammalian epidermis comprises stratified squamous keratinocytes that protect the body from injuries by external factors
FLG expression was significantly decreased in normal human epidermal keratinocytes (NHEKs) transfected with OVOL1 small interfering RNA (siRNA) (Figure 1b), indicating that OVOL1 is intimately involved in FLG expression in NHEKs
The protein levels of OVOL1 either in OVOL1 OE NHEKs or OVOL1-knockdown NHEKs were evaluated by western blotting with an anti-OVOL1 antibody (Supplementary Figures S1A and B); this experiment confirmed that both types of transfection were successful
Summary
Mammalian epidermis comprises stratified squamous keratinocytes that protect the body from injuries by external (e.g., environmental) factors. Our recent study indicates that AHR activation by ketoconazole, a potent AHR ligand,[20] upregulates OVOL1 in NHEKs.[18] we hypothesized that AHR upregulates FLG via OVOL1 and that OVOL1 impairment is involved in FLG downregulation, which may possibly contribute to the development of AD. To test this hypothesis, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown NHEKs using the methods of electroporation and small interfering RNA (siRNA) transfection. It has been already shown that AHR activation induced by coal tar increases FLG expression contributing to the therapeutic effect of coal tar on the development of AD;[21] whether OVOL1 is involved in the upregulation of FLG induced by AHR activation has not been examined
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