Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1.
Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1.
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小鼠脑出血后小胶质细胞的激活和极化：蛋白酶激活受体 1 的作用
DOI：
10.1007/s12975-016-0472-8
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发表时间：
2016-12
影响因子：
6.9
通讯作者：
Xi G
中科院分区：
文献类型：
--
作者：
Wan S;Cheng Y;Jin H;Guo D;Hua Y;Keep RF;Xi G
极化小胶质细胞在神经系统疾病中发挥着双重（有益/有害）作用。然而，在脑出血（ICH）中调节小胶质细胞极化的状态和因素仍不清楚。在本研究中，我们研究了蛋白酶激活受体-1（PAR-1，凝血酶受体）在ICH诱导的小鼠小胶质细胞极化中的作用。雄性野生型（WT）和PAR-1敲除（PAR-1 KO）小鼠接受30 μL自体血液或生理盐水输注至右侧基底神经节。在不同时间点对小鼠实施安乐死，并将脑用于蛋白质印迹和免疫组织化学。一些小鼠进行了磁共振成像。我们发现，ICH诱导小胶质细胞活化和极化。M1表型标记物在脑出血后4 h即达高峰，3d仍保持较高水平，7 d后下降。M2表型标记物的上调晚于M1标记物，在ICH后第1天达到峰值，第7天下降。PAR-1在脑出血后表达上调，主要表达于神经元和小胶质细胞。ICH在PAR-1 KO小鼠中诱导较少的脑肿胀和神经元死亡，这与脑中较少的M1极化和降低的促炎细胞因子水平相关。总之，这些结果表明，极化小胶质细胞发生动态脑出血后，PAR-1在小胶质细胞的激活和极化中发挥作用。
Polarized microglia play a dual (beneficial/detrimental) role in neurological diseases. However, the status and the factors that modulate microglia polarization in intracerebral hemorrhage (ICH) remain unclear. In the present study, we investigated the role of protease-activated receptor-1 (PAR-1, a thrombin receptor) in ICH-induced microglia polarization in mice. Male wild-type (WT) and PAR-1 knockout (PAR-1 KO) mice received an infusion of 30-μL autologous blood or saline into the right basal ganglia. Mice were euthanized at different time points and the brains were used for Western blotting and immunohistochemistry. Some mice had magnetic resonance imaging. We found that ICH induced microglia activation and polarization. M1 phenotypic markers were markedly increased and reached a peak as early as 4 h, remained high at 3 days and decreased 7 days after ICH. M2 phenotypic markers were upregulated later than M1 markers reaching a peak at day 1 and declining by day 7 after ICH. PAR-1 was upregulated after ICH and expressed in the neurons and microglia. ICH induced less brain swelling and neuronal death in PAR-1 KO mice, and this was associated with less M1 polarization and reduced proinflammatory cytokine levels in the brain. In conclusion, these results suggest that polarized microglia occur dynamically after ICH and that PAR-1 plays a role in the microglia activation and polarization.