HDAC expression and activity is upregulated in diseased lupus-prone mice

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-Faslpr (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 20 weeks-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.

Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

“…We are not sure in this study whether HDAC6 inhibition has direct effects on autoreactive B and T cell responses or only indirect effects through down-regulating IFN-a. As one of our previous studies showed that B cells and T cells in another lupus model, Murphy-Roths large lupus-prone mice (MRL/lpr) mice, expressed HDAC6, even at significantly higher levels compared to those in non-lupus mice [17], we speculate that HDAC6 inhibition should have both direct and indirect effects on the alteration of B and T cell responses. To demonstrate this hypothesis, we will create NZB/W mice with pDC-, T cell-and B cell-specific HDAC6 depletion, respectively, in future studies.…”

“…Interestingly, lymphocyte development and numbers in these mice are normal, although there is a mild decrease in the immune response after antigenic stimulation [42]. With regard to SLE, we have previously observed increased expression and activity of HDAC6 within B cells, T cells and glomerular cells of diseased lupus-prone mice [17].…”

“…In our previous studies we have demonstrated that inhibition of HDAC6, a class IIb HDAC, resulted in the amelioration of LN in lupus-prone mice associated with several altered immune responses, with minimal toxicity, suggesting therapeutic potential to treat LN [15][16][17]. SLE is a chronic inflammatory disease that is divided generally into the early autoimmune initiating stage and the later autoimmune effector stage [18][19][20].…”

Autophagy and autoimmunity

“…Further animal studies reveal increased HDAC6 expression in T cells and B cells derived from NZB/W mice [69], and inhibition of HDAC6 reduces lupus pathogenesis in NZB/W mice, which suggest a potential role of HDAC6-dependent selective autophagy in SLE pathogenesis. Therapeutic treatments inhibiting autophagy pathway or autophagy-related proteins may improve SLE clinical outcomes by reducing autoreactive lymphocytes differentiation and their associated functions.…”

Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study

“…Unlike class I HDACs, Class IIa HDACs (HDAC4, 5, 7 and 9) display tissue-specific expression and are involved in a variety of signal transduction pathways [13]. The well-known class IIb HDAC6 controls the status of tubulin and hsp90 acetylation [14]. All these indicates each HDAC enzyme has its unique function in normal cells, therefore, most pan-HDAC inhibitors (HDACIs), which inhibit a broad spectrum of HDACs, exhibited significant toxicity.…”