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AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1–Bcl-6 axis-mediated B-cell differentiation
Signal Transduction and Targeted Therapy ( IF 39.3 ) Pub Date : 2021-09-14 , DOI: 10.1038/s41392-021-00725-x
Ming Yang 1 , Di Long 1 , Longyuan Hu 1 , Zhidan Zhao 1 , Qianwen Li 1 , Yunkai Guo 2 , Zhenghao He 1 , Ming Zhao 1 , Liwei Lu 3 , Fen Li 4 , Hai Long 1 , Haijing Wu 1 , Qianjin Lu 1, 5
Affiliation  

Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19+ B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6–Blimp-1 axis, providing a novel target for SLE treatment.



中文翻译:

B细胞中的AIM2缺乏通过调节Blimp-1-Bcl-6轴介导的B细胞分化来改善系统性红斑狼疮

据报道,黑色素瘤中不存在 2 (AIM2) 是先天免疫细胞中炎性体的一个组成部分。令人惊讶的是,AIM2 由 B 细胞表达,并且在狼疮患者的 B 细胞中观察到更高的 AIM2 表达。迄今为止,AIM2 在 B 细胞中的炎症小体独立功能仍不清楚。在这里,我们报告了人类扁桃体记忆和生发中心 (GC) B 细胞以及狼疮患者循环和皮肤病变中的记忆 B 细胞和浆细胞中 AIM2 的表达增加。B 细胞中 AIM2 的条件性敲除降低了 CD19 +淋巴结和脾脏中的 B 细胞频率,并抑制 KLH 诱导的 IgG1 抗体产生。在一个由鲸蜡素诱导的狼疮小鼠模型中,B 细胞中的 AIM2 缺乏会减轻狼疮症状并降低 GC B 细胞、T 滤泡辅助 (Tfh) 细胞、浆母细胞和浆细胞的频率。此外,人类 B 细胞中 AIM2 的缺失导致 Blimp-1 的表达增加并降低 Bcl-6 的表达。然而,Blimp-1 和 Bcl-6 的沉默对 AIM2 的表达没有显着影响,表明 AIM2 可能是 Blimp-1 和 Bcl-6 的上游调节因子。此外,发现 IL-10 通过 DNA 去甲基化上调 AIM2 表达。总之,我们的研究结果表明 AIM2 在狼疮患者的 B 细胞中高度表达,并通过调节 Bcl-6-Blimp-1 轴促进 B 细胞分化,

更新日期:2021-09-14
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