Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke.
Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke.
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DOI：
10.1523/jneurosci.2102-11.2011
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发表时间：
2011-09-07
期刊：
影响因子：
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通讯作者：
Vexler ZS
中科院分区：
文献类型：
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作者：
Faustino JV;Wang X;Johnson CE;Klibanov A;Derugin N;Wendland MF;Vexler ZS
巨噬细胞被视为缺血性脑损伤的放大器，但产生损伤的巨噬细胞的来源尚不明确。脑内固有巨噬细胞——小胶质细胞在中风中的作用仍存在争议。为了确定小胶质细胞在新生儿局灶性中风后是否产生有害影响，我们在出生后第7天的大鼠大脑中动脉短暂闭塞前，通过脑内注射脂质体包裹的氯膦酸盐选择性地清除这些细胞。在小胶质细胞未受干预的动物中，活化的小胶质细胞对凋亡神经元的吞噬作用较弱，并且清除这些细胞并没有增加凋亡神经元的数量。缺乏小胶质细胞会使缺血再灌注后已经升高的几种细胞因子和趋化因子在脑内的水平升高，还会增加损伤的严重程度和体积，这表明小胶质细胞在亚急性损伤阶段有助于内源性保护。然后，为了确定小胶质细胞中活性氧的积累是否对濒死神经元的吞噬作用产生不利影响并导致损伤，我们再次使用脂质体将还原型谷胱甘肽（GSH）输送到小胶质细胞中。值得注意的是，通过药理学方法提高小胶质细胞内的GSH浓度会诱导这些细胞的脂筏中积累超氧化物，进一步提高巨噬细胞趋化因子在脑内的水平，并加重损伤。综上所述，这些数据表明小胶质细胞是内源性防御机制的一部分，并且虽然抗氧化剂可以保护受损的新生儿大脑，但活化的小胶质细胞中高水平的还原当量（GSH）会引发超氧化物的产生，有利于脂质的重组，放大局部炎症并加重损伤。
Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of injury-producing macrophages is poorly defined. The role of resident brain macrophages—microglial cells—in stroke remains controversial. To determine if microglial cells exert injurious effects after neonatal focal stroke, we selectively depleted these cells with intracerebral injection of liposome-encapsulated clodronate before transient middle cerebral artery occlusion in postnatal day seven rats. Phagocytosis of apoptotic neurons by activated microglia was poor in animals with unmanipulated microglia, and depletion of these cells did not increase the number of apoptotic neurons. Lack of microglia increased the brain levels of several cytokines and chemokines already elevated by ischemia–reperfusion, and also increased the severity and volume of injury, suggesting that microglial cells contribute to endogenous protection during the subacute injury phase. Then, to determine if accumulation of reactive oxygen species in microglia adversely affects phagocytosis of dying neurons and contributes to injury, we delivered reduced glutathione (GSH) into microglia, again using liposomes. Remarkably, pharmacologically increased intracellular GSH concentrations in microglia induced superoxide accumulation in lipid rafts in these cells, further increased the brain levels of macrophage chemoattractants, and exacerbated injury. Taken together, these data show that microglia are part of the endogenous defense mechanisms and that, while antioxidants can protect the injured neonatal brain, high levels of reducing equivalents in activated microglia, GSH, trigger superoxide production, favor the reorganization of lipids, amplify local inflammation and exacerbate injury.