Abstract
Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Fas(lpr) (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.
Highlights
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the activation of autoreactive T and B cells[1,2,3]
We found that Histone deacetylases (HDACs) activity was significantly greater in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells isolated from MRL/lpr mice compared to age-matched C57BL/6 mice (Figure 2)
We found that the expression and activity of class II HDACs (6 and 9) were upregulated in early- and late-diseased MRL/lpr mice compared to age-matched C57BL/6 control mice
Summary
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the activation of autoreactive T and B cells[1,2,3]. During SLE, pathogenic autoantibodies directed against nuclear components, including nucleic acids and histones, are produced contributing to multiorgan inflammation and tissue damage[4]. Studies have shown a number of abnormalities in various stages of B cell development in SLE patients including pre-immune B cell maturation, negative selection, receptor editing, and somatic hypermutation[5]. Aberrant T cell development is thought to contribute to disease in SLE patients. Alterations in the balance and functions of T cell subsets in human SLE patients and murine models include: decreased number and function of regulatory T (Treg) cells, elevated Th1 and Th2 cytokines, and increased numbers of Il-17-producing Th17 cells, which contribute to inflammation[7, 8]
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