Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats
Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats
复制标题
大鼠实验性脑出血后胶质细胞 Tim-3 的负调控抑制炎症因子的分泌并调节小胶质细胞抗炎表型
DOI：
10.1111/cns.13100
复制
发表时间：
2019-06-01
影响因子：
5.5
通讯作者：
Chen, Gang
中科院分区：
文献类型：
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作者：
Chen, Zhou-Qing;Yu, Hao;Chen, Gang
目的探讨Tim-3在脑出血（ICH）继发性脑损伤（SBI）小胶质细胞极化中的作用。方法采用自体全血注入大鼠右侧基底节区建立脑出血模型。原代培养的小胶质细胞用氧合血红蛋白（OxyHb）处理以模拟体外脑出血。在本实验中，Tim-3和重组人TIM-3的特异性siRNA在体内和体外均被利用。结果脑出血后脑组织中Tim-3表达增加，主要分布于小胶质细胞，而神经元和星形胶质细胞未见表达。然而，通过siRNA阻断Tim-3显著减少炎症因子的分泌、神经元变性、神经元细胞死亡和脑水肿。同时，Tim-3的下调促进了脑出血后小胶质细胞表型从M1向M2的转化。脑出血后Tim-3的上调可增强Tim-3与半乳糖凝集素-9（Galectin-9，Gal-9）的相互作用，激活Toll样受体4（TLR-4）通路。Tim-3的表达增加可能与HIF-1 α的激活有关。结论Tim-3可能通过Tim-3/Gal-9和TLR-4信号通路介导了脑出血后SBI的发生，并参与了炎症反应和小胶质细胞极化的发生。
Aims To investigate the critical role of Tim-3 in the polarization of microglia in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Methods An in vivo ICH model was established by autologous whole blood injection into the right basal ganglia in rats. The primary cultured microglia were treated with oxygen-hemoglobin (OxyHb) to mimic ICH in vitro. In this experiment, specific siRNA for Tim-3 and recombinant human TIM-3 were exploited both in vivo and in vitro. Results Tim-3 was increased in the brain after ICH, which mainly distributed in microglia, but not neurons and astrocytes. However, the blockade of Tim-3 by siRNA markedly reduced secretion of inflammatory factors, neuronal degeneration, neuronal cell death, and brain edema. Meanwhile, downregulation of Tim-3 promoted the transformation of microglia phenotype from M1 to M2 after ICH. Furthermore, upregulation of Tim-3 can increase the interaction between Tim-3 and Galectin-9 (Gal-9) and activate Toll-like receptor 4 (TLR-4) pathway after ICH. Increasing the expression of Tim-3 may be related to the activation of HIF-1 alpha. Conclusion Tim-3 may be an important link between neuroinflammation and microglia polarization through Tim-3/Gal-9 and TLR-4 signaling pathways which induced SBI after ICH.