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

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.

The IL‐13–OVOL1–FLG axis in atopic dermatitis

“…The coordinated expression of FLG and other epidermal differentiation proteins is crucial for skin barrier protection . OVOL1 is an upstream transcription factor that regulates FLG expression . It is intriguing that FLG , OVOL1 and IL13 were the three genes most significantly associated with AD among 31 susceptible gene loci reported in a meta‐analysis of genome‐wide association studies .…”

“…The activation of OVOL1 induces its cytoplasmic‐to‐nuclear translocation and up‐regulates FLG and loricrin expression . Notably, IL‐4 and IL‐13 consistently inhibit FLG expression by interfering with OVOL1 signaling . Interleukin‐13 also inhibits the involucrin expression but in an OVOL1‐independent manner and exacerbates barrier dysfunction.…”

“…The lifetime incidence of AD is as high as 20% in the general population . Skin barrier dysfunction is associated with the reduced production of terminal differentiation molecules, such as filaggrin (FLG) . Abnormal skin barrier integrity also causes the increased colonization of microbes, such as Staphylococcus aureus , which further exacerbates skin inflammation .…”

T helper type 2 signatures in atopic dermatitis

“…63 These improvements are associated with the downregulation of the Th2 signatures such as IL-13 and IL-31. 63 OVOL1 is an upstream transcription factor for FLG and LOR expression 29,64 and is one of the susceptibility genes for AD. 18 IL-4 is known to inhibit the activation of OVOL1 by interfering with its cytoplasmic to nuclear translocation.…”

“…18,27 In accordance, FLG expression levels have been reported to be reduced in lesional and nonlesional skin in AD patients. [28][29][30] Ichthyosis vulgaris is also known to be caused by a loss-of-function mutation of the FLG gene. 31 This may explain why AD is significantly comorbid with ichthyosis vulgaris.…”