University of Michigan, Ann Arbor.
University of Michigan, Ann Arbor, and the Second Xiangya Hospital and Central South University, Changsha, China.
Arthritis Rheumatol. 2019 Oct;71(10):1681-1690. doi: 10.1002/art.40931. Epub 2019 Aug 12.
We previously identified a role for EZH2, a transcriptional regulator in inducing proinflammatory epigenetic changes in lupus CD4+ T cells. This study was undertaken to investigate whether inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.
EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and messenger RNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by intraperitoneal 3'-deazaneplanocin (DZNep) administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-double-stranded DNA (anti-dsDNA) antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.
EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibition of EZH2 by DZNep was confirmed by significant reduction of EZH2 and H3K27me3 in splenocytes. Inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy. Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep-treated mice. Concentrations of circulating cytokines and chemokines, including tumor necrosis factor, interferon-γ, CCL2, RANTES/CCL5, interleukin-10 (IL-10), keratinocyte-derived chemokine/CXCL1, IL-12, IL-12p40, and CCL4/macrophage inflammatory protein 1β, were decreased in DZNep-treated mice.
EZH2 is up-regulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option for lupus patients.
我们之前发现，转录调节因子 EZH2 可诱导狼疮 CD4+T 细胞发生促炎表遗传改变。本研究旨在探讨抑制 EZH2 是否能改善 MRL/lpr 狼疮样小鼠的疾病。
采用流式细胞术和信使 RNA 表达数据评估狼疮患者多种细胞类型中的 EZH2 表达水平。通过腹腔内给予 3'-去氮杂胞苷（DZNep），采用预防和治疗两种治疗模型，实现 MRL/lpr 小鼠 EZH2 的抑制。评估 DZNep 对动物存活率、抗双链 DNA（抗 dsDNA）抗体产生、蛋白尿、肾脏组织病理学、细胞因子产生以及 T 和 B 细胞数量和比例的影响。
狼疮患者全血、中性粒细胞、单核细胞、B 细胞和 CD4+T 细胞中 EZH2 的表达水平增加。在 MRL/lpr 小鼠中，DZNep 抑制 EZH2 可通过脾细胞中 EZH2 和 H3K27me3 的显著减少得到证实。在疾病发病前或发病后用 DZNep 抑制 EZH2，可提高存活率并显著减少抗 dsDNA 抗体的产生。DZNep 治疗的小鼠肾脏受累、脾肿大和淋巴结病明显减轻。DZNep 治疗的小鼠淋巴细胞增生和双阴性 T 细胞数量明显减少。DZNep 治疗的小鼠循环细胞因子和趋化因子的浓度降低，包括肿瘤坏死因子、干扰素-γ、CCL2、RANTES/CCL5、白细胞介素-10（IL-10）、角质细胞衍生的趋化因子/CXCL1、IL-12、IL-12p40 和 CCL4/巨噬细胞炎症蛋白 1β。
EZH2 在狼疮患者的多种细胞类型中上调。EZH2 的治疗性抑制可消除 MRL/lpr 狼疮样小鼠的疾病，表明 EZH2 抑制剂可作为狼疮患者的一种新的治疗选择。
