BET蛋白抑制剂JQ1对MRL/lpr狼疮小鼠外周B细胞分化的影响  

Effect of BET inhibitor JQ1 on peripheral B cell differentiation of MRL/lpr lupus mice

作　　者：曾珊[1] 肖游君[1] 邱茜[1] 李昊[1] 徐思琪 王竞男[1] 石茂华 梁柳琴[1] 许韩师[1] ZENG Shan;XIAO Youjun;QIU Qian;LI Hao;XU Siqi;WANG Jingnan;SHI Maohua;LIANG Liuqin;XU Hanshi(Department of Rheumatology and Clinical Immunology,the First Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China)

机构地区：[1]中山大学附属第一医院风湿免疫科,广州510080

出　　处：《中国免疫学杂志》2023年第7期1345-1350,共6页Chinese Journal of Immunology

基　　金：国家自然科学基金青年科学基金项目(81701611);广州市民生科技攻关计划项目(201803010042)。

摘　　要：目的:探讨BET蛋白抑制剂JQ1对MRL/lpr狼疮小鼠外周B细胞分化的影响及其治疗作用。方法:12周龄MRL/lpr小鼠分别腹腔注射JQ150 mg/(kg·d)或10%DMSO;每2周检测24 h尿蛋白定量;6周后检测血清中尿素氮(BUN)、肌酐(Cr)、补体C3、补体C4、抗ds-DNA抗体、ANA及IgG、IgG1、IgG2a、IgM等免疫球蛋白水平;PAS染色观察肾脏组织病理学改变,免疫荧光染色观察IgG和C3免疫复合物沉积情况。利用流式细胞术检测小鼠B细胞各亚群细胞的比例;RT-qPCR检测脾脏prdm1 mRNA表达水平。结果:与DMSO组相比,JQ1治疗组小鼠24 h尿蛋白定量显著减少,血清BUN、Cr水平明显降低,补体C3、C4水平明显升高,抗ds-DNA抗体、ANA以及IgG、IgG1、IgG2a和IgM等免疫球蛋白水平明显降低;此外,JQ1治疗组小鼠肾小球、肾血管的病理损害程度均明显减轻,肾脏IgG和C3免疫复合物沉积显著减少。同时,JQ1治疗组小鼠脾脏、淋巴结、外周血B细胞中浆细胞和记忆B细胞亚群的比例显著下降;JQ1治疗亦显著抑制狼疮小鼠B细胞内调节浆细胞分化的关键转录因子prdm1 mRNA表达。结论:BET蛋白抑制剂JQ1对MRL/lpr狼疮小鼠具有显著的治疗作用,通过抑制Blimp1表达进而调节浆细胞分化可能是其发挥治疗作用的机制之一。BET蛋白可能是SLE治疗的新靶标。Objective:To investigate the role of bromodomain and extra-terminal domain(BET)protein in regulating peripheral B cell differentiation and the therapeutic effect of BET inhibitor JQ-1 on MRL/lpr spontaneous lupus mice.Methods:12-week-old MRL/lpr mice were intraperitoneally injected with JQ150 mg(/kg·d)or 10%DMSO;24 hour urine protein quantification every 2 weeks;serum urea nitrogen(BUN),creatinine(Cr),complement C3,complement C4,anti-ds-DNA antibody,ANA and IgG,IgG1,IgG2a,IgM were detected after 6 weeks;PAS and immunofluorescence staining were used to observe the pathological changes of kidney tissue and IgG and C3 immune complex deposition,respectively.Flow cytometry was used to detect the proportion of each subgroup of mouse B cells from spleen,lymph nodes,and peripheral blood.prdm1 mRNA expression level was measured by RT-qPCR.Results:Compared with the DMSO group,the 24 hour urine protein quantification of mice in the JQ1-treated group was significantly reduced,the BUN and Cr levels were significantly reduced;the levels of complement C3 and C4 were significantly increased,and the levels of anti-ds-DNA antibodies,ANA,IgG,IgG1,IgG2a,and IgM were also significantly decreased.JQ1 treatment also improved the severity of pathological damage of the glomerulus and renal blood vessels,and deposition of IgG and C3 immune complexes in the kidney.Interestingly,JQ1 treatment resulted in reduction of the percentages of plasma cell and memory B cells subsets in spleen,lymph nodes,and peripheral blood B cells.Moreover,JQ1 treatment suppressed the expression of prdm1 mRNA,a critical transcript factor that regulated plasma cell differentiation.Conclusion:The BET inhibitor JQ1 exhibits a therapeutic potential for MRL/lpr lupus mice through,at least in part,regulating plasma cell differentiation via inhibiting Blimp1 expression.BET protein might be a novel target for SLE treatment.

关 键 词：BET蛋白抑制剂 MRL/lpr狼疮小鼠 B细胞 

分 类 号：R593.24[医药卫生—内科学]