Identification of Histone Deacetylase Inhibitor Targeting Type I Interferon and B Cell Abnormalities in Systemic Lupus Erythematosus.

Abstract

Systemic lupus erythematosus (SLE) is characterized by increased Type I interferon (IFN-I) and autoantibody production. This study aimed to identify drugs that can inhibit both IFN-I and autoantibody production. We identified an inhibitor of IFN-I production from a chemical library. Subsequently, we examined its efficacy and underlying mechanisms in suppressing the expression and phosphorylation of upstream signaling molecules for IFN-I production and the differentiation of B cells into plasma cells. Additionally, we examined whether it could alleviate disease severity in SLE-prone mice. We showed that vorinostat, a clinically approved pan-histone deacetylase (HDAC) inhibitor, inhibited both IFN-I production and plasma cell differentiation. Vorinostat suppressed IFN-I production by inhibiting TBK1 phosphorylation and the subsequent IRF3 nuclear translocation and suppressed plasma cell differentiation by inhibiting the expression of essential transcriptional factors for plasma cells. Notably, inhibiting HDAC6 suppressed IFN-I induction and plasma cell differentiation. Furthermore, vorinostat ameliorated lung inflammation in STING-associated vasculopathy with onset in infancy mice by decreasing IFN-I and alleviated the mortality and severity of renal disease in New Zealand Black/White F1 mice by suppressing IFN-I induction and B cell differentiation. Vorinostat ameliorates the severity of disease in SLE-prone mice by simultaneously suppressing IFN-I production and plasma cell differentiation by targeting HDAC6. Thus, vorinostat is a promising therapeutic agent for SLE and may benefit patients with SLE requiring more effective and better-tolerated therapies.