Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus
Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus
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DOI：
10.1016/s0960-9822(98)70016-8
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发表时间：
1998-01-01
期刊：
影响因子：
9.2
通讯作者：
Tsirka, SE
中科院分区：
文献类型：
--
作者：
Rogove, AD;Tsirka, SE
背景：脑损伤引起局部基因表达、细胞形态和行为的显著变化。小胶质细胞的激活是中枢神经系统（CNS）损伤后的早期事件，但尚未确定这种激活是否在神经元死亡中起因果作用。我们使用兴奋性毒素介导的脑损伤模型系统，结合内源性肽因子，研究了这个问题结果：使用巨噬细胞/小胶质细胞抑制因子（macrophage/microglial inhibiting factor，MIF），我们抑制了小胶质细胞的激活，这种激活通常伴随着兴奋性毒性损伤。在细胞培养研究中，我们发现，这种抑制阻断了小胶质细胞来源的组织纤溶酶原激活物（tPA）的快速释放，tPA是一种由神经元和小胶质细胞产生的细胞外丝氨酸蛋白酶，我们以前已经确定它是兴奋性毒素诱导的神经元死亡的关键步骤。最后，输注MIF到小鼠大脑兴奋性毒性损伤前导致保护神经元细胞death.Conclusions：我们的研究结果表明，小胶质细胞进行神经毒性作用时，兴奋性毒性损伤发生在中枢神经系统。他们还表明，从小胶质细胞释放的tPA在触发神经退行性变中具有关键作用。
Background: Injury to the brain induces dramatic local changes in gene expression, cellular morphology and behavior. Activation of microglial cells occurs as an early event after central nervous system (CNS) injury, but it has not been determined whether such activation plays a causal role in neuronal death, We have investigated this question using an excitotoxin-mediated brain injury model system, in conjunction with an endogenous peptide factor (macrophage/microglial inhibiting factor, MIF) that ablates microglial contribution to the cascade.Results: Using MIF, we inhibited the microglial activation that normally follows excitotoxic injury. In cell culture studies, we found that such inhibition blocked the rapid release of microglia-derived tissue plasminogen activator (tPA), an extracellular serine protease made by both neurons and microglia, which we had previously identified as mediating a critical step in excitotoxin-induced neuronal death. Finally, infusion of MIF into the mouse brain prior to excitotoxic insult resulted in the protection of neurons from cell death.Conclusions: Our results demonstrate that microglia undertake a neurotoxic role when excitotoxic injury occurs in the CNS. They also suggest that the tPA released from microglia has a critical role in triggering neurodegeneration.