Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China.
Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China.
Int Immunopharmacol. 2023 Jun;119:110155. doi: 10.1016/j.intimp.2023.110155. Epub 2023 Apr 10.
The aim of this study was to elucidate the role of enhancer of zeste homolog 2 (EZH2) in the breakdown of B cell immune tolerance and production of autoantibodies in systemic lupus erythematosus (SLE), and to explore the therapeutic effects of EZH2 inhibition on lupus.
Peripheral blood mononuclear cells (PBMCs) were collected from new-onset SLE patients for flow cytometric analysis. Pristane-induced lupus mice were constructed, and the EZH2 inhibitor was administrated by intraperitoneal injection to treat lupus mice. Blood and urine were collected from lupus mice to detect autoantibodies and proteinuria, and renal pathology scores were assessed. Mouse spleen B cells were sorted with magnetic beads and subjected to flow cytometric apoptosis detection, real time quantitative PCR (RT-qPCR), and western blotting (WB).
EZH2 expression was elevated in diverse B-cell subsets in both SLE patients and pristane-induced lupus mice. The EZH2 inhibitor attenuated lupus-like symptoms and dampened autoantibody production in pristane-induced lupus mice. Inhibition of EZH2 also reduced autoantibody secretion by plasma cells from lupus patients. Mechanistically, EZH2 mediated the impaired apoptosis of autoreactive B cells and the differentiation of autoantibody producing plasma cells by inhibiting multiple cyclin-dependent kinase inhibitor (CKI) genes.
EZH2 mediated the breakdown of B-cell peripheral immune tolerance by inhibiting CKI genes and participated in the generation of autoantibodies in SLE. EZH2 inhibition could serve as a promising drug intervention for the treatment of SLE.
本研究旨在阐明增强子结合蛋白 2（EZH2）在系统性红斑狼疮（SLE）中 B 细胞免疫耐受破坏和自身抗体产生中的作用，并探讨 EZH2 抑制对狼疮的治疗作用。
收集新诊断的 SLE 患者的外周血单个核细胞（PBMC）进行流式细胞术分析。构建了松柏醇诱导的狼疮小鼠，并通过腹腔注射给予 EZH2 抑制剂治疗狼疮小鼠。收集狼疮小鼠的血液和尿液，检测自身抗体和蛋白尿，并评估肾脏病理评分。用磁珠分选小鼠脾 B 细胞，进行流式细胞术凋亡检测、实时定量 PCR（RT-qPCR）和 Western blot（WB）。
EZH2 在 SLE 患者和松柏醇诱导的狼疮小鼠的多种 B 细胞亚群中表达升高。EZH2 抑制剂减轻了狼疮样症状并抑制了松柏醇诱导的狼疮小鼠的自身抗体产生。EZH2 抑制剂还减少了狼疮患者浆细胞的自身抗体分泌。机制上，EZH2 通过抑制多个细胞周期蛋白依赖性激酶抑制剂（CKI）基因来介导自身反应性 B 细胞的凋亡受损和自身抗体产生的浆细胞分化。
EZH2 通过抑制 CKI 基因介导 B 细胞外周免疫耐受的破坏，并参与 SLE 中自身抗体的产生。EZH2 抑制可能成为治疗 SLE 的一种有前途的药物干预措施。
