Background: Atopic dermatitis (AD), a persistent inflammatory condition of the skin, presents features of pruritus, skin barrier dysfunction, and immune dysregulation, affecting millions globally with increasing prevalence. Acetate (Ace), a short-chain fatty acid with immunomodulatory and barrier-protective properties, has been reported to enhance skin barrier integrity in AD, but its precise molecular mechanisms remain unclear. This study aims to investigate the therapeutic potential of Ace and its underlying mechanism in an AD mouse model. Methods: An AD mouse model was established via repeated topical application of 2,4-dinitrochlorobenzene (DNCB) and treated with Ace sodium. Macroscopic situation, AD severity, and dorsal tissue pathology were evaluated. Skin mRNA expression levels of inflammatory factors, histone deacetylase 2 (HDAC2), and signal transducer and activator of transcription 1 (STAT1), as well as HDAC2-STAT1 promoter correlation, were examined using chromatin immunoprecipitation. CD4+ T cells from healthy mouse splenocytes were transfected with HDAC2/STAT1 overexpression plasmids, and treated under Th17-inducing conditions with Ace. Th17/regulatory T (Treg) in splenocytes was assessed by flow cytometry. Results: Ace mitigated DNCB-induced dryness, erosion of dorsal skin, and ear redness. Furthermore, Ace downregulated the expression levels of pro-inflammatory factors and HDAC2 in the dorsal skin tissue, reduced the proportion of Th17 cells in the splenocytes, and promoted the expression of STAT1. Chromatin immunoprecipitation confirmed the binding of HDAC2 to the STAT1 promoter. Ace also suppressed the Th17 differentiation of CD4+ T cells, which was counteracted by HDAC2 overexpression, while STAT1 overexpression offset the regulatory effect of HDAC2 overexpression. Conclusions: Ace mitigates DNCB-induced AD by inhibiting HDAC2 to activate STAT1 and block Th17 differentiation, uncovering a novel HDAC2-STAT1-Th17 regulatory axis and providing a promising metabolite-based therapeutic strategy for AD.
He et al. (Thu,) studied this question.