TJ-M2010-5, a novel MyD88 inhibitor, corrects R848-induced lupus-like immune disorders of B cells in vitro
TJ-M2010-5, a novel MyD88 inhibitor, corrects R848-induced lupus-like immune disorders of B cells in vitro
复制标题
TJ-M2010-5是一种新型MyD88抑制剂，可在体外纠正R848诱导的B细胞狼疮样免疫紊乱
DOI：
10.1016/j.intimp.2020.106648
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发表时间：
2020
影响因子：
5.6
通讯作者：
Fengchao Jiang
中科院分区：
文献类型：
--
作者：
Zhimiao Zou;Dunfeng Du;Yan Miao;Yang;Yalong Xie;Zeyang Li;Liang Zhou;Limin Zhang;Ping Zhou;Fengchao Jiang
B细胞过度活跃参与系统性红斑狼疮（SLE）的发展。B细胞中的Toll样受体7（TLR 7）在SLE的发病机制中起关键作用。以往的研究主要集中在B细胞在TLR 7/MyD 88信号传导中的内在作用，从而对免疫激活、自身抗体产生和全身炎症的影响。然而，这种免疫疾病的可行治疗方法仍有待发现。已经研究的体外细胞反应可能在SLE中一些重要自身抗体的产生中起核心作用。我们成功地利用R848在体外建立了狼疮样B细胞模型;这些B细胞被过度激活，分化为浆细胞，逃避凋亡，大量增殖，并产生大量的自身抗体和细胞因子。在本研究中，我们发现我们实验室先前合成的新型MyD 88抑制剂TJ-M2010-5似乎可以抑制B细胞的狼疮样状态，包括过度活化、大量增殖、向浆细胞分化以及自身抗体和细胞因子的过度产生。TJ-M2010-5还可诱导B细胞凋亡。此外，TJ-M2010-5还能显著抑制NF-κB和MAPK信号通路。综上所述，TJ-M2010-5可能通过阻断TLR 7/MyD 88/NF-κB和TLR 7/MyD 88/MAPK信号通路，纠正R848诱导的B细胞狼疮样免疫紊乱。
B cell hyperactivities are involved in the development of systemic lupus erythematosus (SLE). Toll-like receptor 7 (TLR7) in the B cells plays a pivotal role in the pathogenesis of SLE. Previous studies have focused on the intrinsic role of B cells in TLR7/MyD88 signaling and consequently on immune activation, autoantibody pro-duction, and systemic inflammation. However, a feasible treatment for this immune disorder remains to be discovered. The in vitro cellular response that have been studied likely plays a central role in the production of some important autoantibodies in SLE. We successfully used R848 to build a lupus-like B cell model in vitro; these B cells were overactivated, differentiated into plasma cells, escaped apoptosis, massively proliferated, and produced large amounts of autoantibodies and cytokines. In the present study, we found that TJ-M2010-5, a novel MyD88 inhibitor previously synthesized in our lab, seemed to inhibit the lupus-like condition of B cells, including overactivation, massive proliferation, differentiation into plasma cells, and overproduction of auto-antibodies and cytokines. TJ-M2010-5 also induce B cells apoptosis. Furthermore, TJ-M2010-5 was found to remarkably inhibit NF-κB and MAPK signaling. In summary, TJ-M2010-5 might correct R848-induced lupus-like immune disorders of B cells by blocking the TLR7/MyD88/NF-κB and TLR7/MyD88/MAPK signaling pathways.