Microglial activation and dopaminergic cell injury:: An in vitro model relevant to Parkinson's disease
Microglial activation and dopaminergic cell injury:: An in vitro model relevant to Parkinson's disease
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DOI：
10.1523/jneurosci.21-21-08447.2001
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发表时间：
2001-11-01
影响因子：
5.3
通讯作者：
Appel, SH
中科院分区：
文献类型：
--
作者：
Le, WD;Rowe, D;Appel, SH
小胶质细胞活化和氧化应激是帕金森病（PD）病理学的重要组成部分，但它们在疾病发病机制中的确切作用尚不清楚。我们已经开发了一种黑质损伤的体外模型，其中脂多糖诱导的小胶质细胞活化导致多巴胺能细胞系（MES 23.5细胞）和多巴胺能神经元在原代中脑细胞培养物中的损伤。在低剂量多巴醌或H2 O2修饰的多巴胺能细胞膜而非胆碱能细胞膜存在下，小胶质细胞也被PD IgG激活。活化需要小胶质细胞Fc γ R受体，如通过来自Fc γ R-/-小鼠的PD IgG Fab片段或小胶质细胞缺乏活化所证明的。虽然小胶质细胞活化导致几种细胞因子和活性氧的释放，但似乎只有一氧化氮和H2 O2介导小胶质细胞诱导的多巴胺能细胞损伤。这些研究表明小胶质细胞在多巴胺能细胞损伤中的重要作用，并提供了一种机制，使PD中的免疫/炎症反应可以相对特异性地靶向多巴胺能细胞的氧化损伤。
Microglial activation and oxidative stress are significant components of the pathology of Parkinson's disease (PD), but their exact contributions to disease pathogenesis are unclear. We have developed an in vitro model of nigral injury, in which lipopolysaccharide-induced microglial activation leads to injury of a dopaminergic cell line (MES 23.5 cells) and dopaminergic neurons in primary mesencephalic cell cultures. The microglia are also activated by PD IgGs in the presence of low-dose dopa-quinone- or H2O2-modified dopaminergic cell membranes but not cholinergic cell membranes. The activation requires the microglial Fc gammaR receptor as demonstrated by the lack of activation with PD IgG Fab fragments or microglia from Fc gammaR-/- mice. Although microglial activation results in the release of several cytokines and reactive oxygen species, only nitric oxide and H2O2 appear to mediate the microglia-induced dopaminergic cell injury. These studies suggest a significant role for microglia in dopaminergic cell injury and provide a mechanism whereby immune/inflammatory reactions in PD could target oxidative injury relatively specifically to dopaminergic cells.