The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain.
The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain.
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DOI：
10.2353/ajpath.2009.080661
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发表时间：
2009-02
期刊：
影响因子：
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通讯作者：
Chen Zhang;J. An;D. Strickland;M. Yepes
中科院分区：
文献类型：
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作者：
Chen Zhang;J. An;D. Strickland;M. Yepes
小胶质细胞是中枢神经系统（CNS）的免疫细胞，在脑缺血等病理情况下被激活。组织型纤溶酶原激活剂（tPA）是一种存在于血管内间隙和中枢神经系统的丝氨酸蛋白酶。低密度脂蛋白受体相关蛋白1 （LRP1）是低密度脂蛋白受体基因家族的成员，存在于神经元、星形胶质细胞和小胶质细胞中。本研究探讨了tPA与小胶质细胞LRP1之间的相互作用是否在脑缺血诱导的小胶质细胞激活中起作用。我们发现大脑中动脉闭塞（MCAO）诱导野生型和纤溶酶原缺陷（Plg(-/-)）小鼠的小胶质细胞活化。相反，在tPA缺乏（tPA(-/-)）小鼠和小胶质细胞缺乏LRP1 （macLRP(-)）小鼠中，mcao诱导的小胶质细胞激活显著降低。我们观察到，当tPA（-/-）小鼠在MCAO后接受小鼠tPA治疗时，小胶质细胞的激活显著增加。相比之下，用tPA治疗macLRP（-）小鼠对小胶质细胞的激活程度没有影响。最后，在macLRP（-）小鼠和macLRP（-）小胶质细胞中，缺血损伤的体积和诱导型一氧化氮合酶的产生均显著减少。总之，我们的研究结果表明，tPA和LRP1之间的相互作用诱导小胶质细胞激活，并在缺血脑中产生炎症反应，这表明tPA在中枢神经系统中具有细胞因子样作用。
Microglia are the immune cells of the central nervous system (CNS) that become activated in response to pathological situations such as cerebral ischemia. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in the intravascular space and the CNS. The low-density lipoprotein receptor-related protein 1 (LRP1) is a member of the low-density lipoprotein receptor gene family found in neurons, astrocytes, and microglia. The present study investigated whether the interaction between tPA and microglial LRP1 plays a role in cerebral ischemia-induced microglial activation. We found that middle cerebral artery occlusion (MCAO) induces microglial activation in both wild-type and plasminogen-deficient (Plg(-/-)) mice. In contrast, MCAO-induced microglial activation is significantly decreased in tPA-deficient (tPA(-/-)) mice and in mice that lack LRP1 in microglial cells (macLRP(-)). We observed a significant increase in microglial activation when tPA(-/-) mice received treatment with murine tPA after MCAO. In contrast, treatment of macLRP(-) mice with tPA did not have an effect on the extent of microglial activation. Finally, both the volume of the ischemic lesion as well as inducible nitric oxide synthase production were significantly decreased in macLRP(-) mice and macLRP(-) microglia. In summary, our results indicate that the interaction between tPA and LRP1 induces microglial activation with the generation of an inflammatory response in the ischemic brain, suggesting a cytokine-like role for tPA in the CNS.