Department of Biotechnology, Dalian Medical University, Dalian, China.
Department of Clinical Laboratory, Xinhua Hospital Affiliated to Dalian University, Dalian, China.
J Cell Biochem. 2019 Apr;120(4):5160-5168. doi: 10.1002/jcb.27792. Epub 2018 Oct 15.
Multiple sclerosis (MS) is a highly disabling demyelinating disease, which mainly affects young adults and is difficult to cure. Activated microglia may be involved in the process of neuronal cell damage and release inflammatory cytokines to injure neurons. Rapamycin (RAPA), an immunosuppressant, can induce autophagy in microglia to delay the process of the disease. As an inhibitor of NLRP3, MCC950 (CP-456773) can regulate the activation of inflammasome. An experimental autoimmune encephalomyelitis model, a disease model of MS, was established to detect the role of activated microglia in the dynamic evolution of MS. Our research showed that RAPA and MCC950 could reduce both the clinical symptom and the release of cytokines in immune cells. MCC950 reduced interleukin-1β (IL-1β) production in vivo and enhanced the effect of RAPA. We hypothesized that inflammation and demyelination in the central nervous system can be reduced by inhibiting the immune response mediated by microglia. This study provides theoretical support to the therapeutic evaluation of RAPA and MCC950 to make the mammalian targets of RAPA and NLRP3 the therapeutic targets of MS.
多发性硬化症（MS）是一种高度致残的脱髓鞘疾病，主要影响年轻人，且难以治愈。活化的小胶质细胞可能参与神经元细胞损伤过程，并释放炎症细胞因子损伤神经元。雷帕霉素（RAPA）是一种免疫抑制剂，可诱导小胶质细胞自噬，从而延缓疾病进程。NLRP3 的抑制剂 MCC950（CP-456773）可调节炎症小体的激活。我们建立了实验性自身免疫性脑脊髓炎模型（MS 的疾病模型），以检测活化的小胶质细胞在 MS 动态演变中的作用。我们的研究表明，RAPA 和 MCC950 均可减轻临床症状和免疫细胞中细胞因子的释放。MCC950 减少了体内白细胞介素-1β（IL-1β）的产生，并增强了 RAPA 的作用。我们假设通过抑制小胶质细胞介导的免疫反应，可以减轻中枢神经系统的炎症和脱髓鞘。这项研究为 RAPA 和 MCC950 的治疗评估提供了理论支持，使哺乳动物雷帕霉素靶蛋白和 NLRP3 成为 MS 的治疗靶点。
