Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurosurgery, Nantong No.1 People Hospital, Nantong, China.
CNS Neurosci Ther. 2019 Jun;25(6):674-684. doi: 10.1111/cns.13100. Epub 2019 Jan 24.
To investigate the critical role of Tim-3 in the polarization of microglia in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI).
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.
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-1α.
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.
探讨 Tim-3 在脑出血（ICH）继发性脑损伤（SBI）中诱导小胶质细胞极化中的关键作用。
通过向大鼠基底节内自体全血注射建立体内 ICH 模型。用氧合血红蛋白（OxyHb）处理原代培养的小胶质细胞，在体外模拟 ICH。在此实验中，分别在体内和体外利用 Tim-3 的特异性 siRNA 和重组人 TIM-3 进行研究。
ICH 后大脑中 Tim-3 增加，主要分布在小胶质细胞中，而不是神经元和星形胶质细胞中。然而，通过 siRNA 阻断 Tim-3 可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，下调 Tim-3 可促进 ICH 后小胶质细胞表型从 M1 向 M2 的转化。此外，上调 Tim-3 可增加 ICH 后 Tim-3 与半乳糖凝集素-9（Gal-9）之间的相互作用，并激活 Toll 样受体 4（TLR-4）途径。增加 Tim-3 的表达可能与 HIF-1α 的激活有关。
Tim-3 可能通过 Tim-3/Gal-9 和 TLR-4 信号通路在神经炎症和小胶质细胞极化之间成为 ICH 后 SBI 的重要联系。
