Selective HDAC6 inhibitor decreases lupus in mice

Abstract

Abstract Histone deacetylase 6 (HDAC6) is a Class IIb HDACs enzyme primarily residing in the cytoplasm. HDAC6 alters gene transcription by removing acetyl groups from lysine residues on transcription factors. We, and others, have previously demonstrated that HDAC6 expression is increased in systemic lupus erythematosus (SLE) patients and animal models of lupus and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Importantly, we sought to delineate the cellular and molecular mechanism(s) of action for the HDAC6 inhibitor. We treated 20-week-old early-diseased NZB/W F1 (lupus) female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for five weeks. At the termination of the study, our results showed a reduced germinal center B cell response, decreased T follicular helper cells and diminished IFN-g production from T helper cells in splenic tissue. Additionally, we found the IFNa-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taking together, these studies show selective HDAC inhibition decreased several parameters of disease pathogenesis in lupus prone mice. The decrease was in part due to inhibition of autoreactive B cell differentiation. Studies are currently underway to define further the mechanism of how HDAC6 inhibits auto-reactive B cell differentiation.