Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, China.
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, China.
Int Immunopharmacol. 2020 Aug;85:106648. doi: 10.1016/j.intimp.2020.106648. Epub 2020 Jun 5.
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 production, 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 autoantibodies 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.
B 细胞过度活跃参与了系统性红斑狼疮（SLE）的发展。B 细胞中的 Toll 样受体 7（TLR7）在 SLE 的发病机制中起着关键作用。以前的研究集中在 B 细胞内在的 TLR7/MyD88 信号转导作用，以及随之而来的免疫激活、自身抗体产生和全身炎症。然而，一种可行的治疗这种免疫紊乱的方法仍有待发现。体外细胞反应可能在 SLE 中某些重要自身抗体的产生中起着核心作用。我们成功地使用 R848 在体外构建了狼疮样 B 细胞模型；这些 B 细胞过度激活、分化为浆细胞、逃避凋亡、大量增殖，并产生大量自身抗体和细胞因子。在本研究中，我们发现 TJ-M2010-5，一种以前在我们实验室合成的新型 MyD88 抑制剂，似乎可以抑制 B 细胞的狼疮样状态，包括过度激活、大量增殖、分化为浆细胞以及自身抗体和细胞因子的过度产生。TJ-M2010-5 还诱导 B 细胞凋亡。此外，还发现 TJ-M2010-5 显著抑制 NF-κB 和 MAPK 信号通路。总之，TJ-M2010-5 可能通过阻断 TLR7/MyD88/NF-κB 和 TLR7/MyD88/MAPK 信号通路来纠正 R848 诱导的 B 细胞狼疮样免疫紊乱。
