Histone deacetylase 3 inhibition alleviates 2,4-dinitrochlorobenzene-in-duced atopic dermatitis via epigenetically upregulating Nrf2/HO-1 signaling pathway

Atopic dermatitis (AD) is a frequent skin disorder that is associated with immune dysfunction and skin inflammation. Histone deacetylase 3 (HDAC3) possesses strong immune and inflammatory modulatory proper-ties in multiple diseases. However, the role and mechanism of HDAC3 in AD remain unknown. Here, we reported that HDAC3 expression was aberrantly upregulated in 2,4-dinitrochlorobenzene (DNCB)-induced lesional AD skin in mice. Inhibition of HDAC3 by RGFP966 protected against DNCB-induced AD, indicated by improved histological damages, relieved inflammatory and immune dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway activity in lesional AD skin was significantly decreased and RGFP966 attenuated the decrease. Inhibition of Nrf2/HO-1 signaling pathway via Nrf2 inhibitor ML385 blunted anti-AD effect of RGFP966 in DNCB-treated mice. Mechanistically, RGFP966 promoted Nrf2 expression and upregulated H3K27ac deposition on the promoter region of Nrf2. Collectively, HDAC3 inhibition protects against AD via epigenetically activating Nrf2 transcription to upregulate Nrf2/HO-1 signaling pathway activity. HDAC3 may act as a promising therapeutic target for the treatment of AD.

Automated summary

This study found that inhibiting HDAC3 can protect the skin from atopic dermatitis by activating the Nrf2 transcription to upregulate Nrf2/HO-1 signaling pathway activity.