Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.
Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.
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DOI：
10.4049/jimmunol.181.10.7194
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发表时间：
2008-11-15
期刊：
影响因子：
--
通讯作者：
Hong JS
中科院分区：
文献类型：
--
作者：
Hu X;Zhang D;Pang H;Caudle WM;Li Y;Gao H;Liu Y;Qian L;Wilson B;Di Monte DA;Ali SF;Zhang J;Block ML;Hong JS
已知神经元死亡会引发反应性小胶质细胞增生。然而，关于小胶质细胞被损伤的神经元激活的方式以及小胶质细胞增生如何参与神经变性的方式知之甚少。在这项研究中，我们描述了巨噬细胞Ag复合物-1（MAC 1），β2整合素家族的成员，在介导反应性小胶质细胞增生和促进多巴胺能（DA能）神经变性的帕金森病的1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）模型中的重要作用。MAC 1缺乏可显著减弱MPTP或1-甲基-4-苯基碘化吡啶（MPP+）诱导的DA能神经元变性。通过将来自MAC 1-/-或MAC 1 +/+小鼠的小胶质细胞添加回富含MAC 1 +/+神经元的培养物而创建的重建实验表明，具有功能性MAC 1表达的小胶质细胞对于小胶质细胞增强的神经毒性是必需的。在体内和体外形态学和蛋白质印迹研究表明，MPTP/MPP+产生较少的小胶质细胞活化的MAC 1-/-小鼠比MAC 1 +/+小鼠。进一步的机制研究表明，MPP+介导的超氧化物产生的增加减少MAC 1-/-神经胶质细胞培养物相比，MAC 1 +/+文化。MAC 1-/-小胶质细胞中超氧化物的产生受阻可能与胞质NADPH氧化酶（PHOX）亚基（p47 phox）缺乏向膜的易位有关。此外，与神经元加MAC 1 +/+小胶质细胞共培养物相比，神经元加MAC 1-/-小胶质细胞共培养物中PGE 2的产生显著降低。综上所述，这些结果表明，MAC 1在MPTP/MPP+诱导的反应性小胶质细胞增生中起关键作用，并进一步支持以下假设：反应性小胶质细胞增生是导致帕金森病中观察到的进行性DA能神经变性的自我延续周期中的重要步骤。
Neuronal death is known to trigger reactive microgliosis. However, little is known regarding the manner by which microglia are activated by injured neurons and how microgliosis participates in neurodegeneration. In this study we delineate the critical role of macrophage Ag complex-1 (MAC1), a member of the β2 integrin family, in mediating reactive microgliosis and promoting dopaminergic (DAergic) neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. MAC1 deficiency greatly attenuated the DAergic neurodegeneration induced by MPTP or 1-methyl-4-phenyl-pyridium iodide (MPP+) exposure both in vivo and in vitro, respectively. Reconstituted experiments created by adding microglia from MAC1–/– or MAC1+/+ mice back to MAC1+/+ neuron-enriched cultures showed that microglia with functional MAC1 expression was mandatory for microglia-enhanced neurotoxicity. Both in vivo and in vitro morphological and Western blot studies demonstrated that MPTP/MPP+ produced less microglia activation in MAC1–/– mice than MAC1+/+ mice. Further mechanistic studies revealed that a MPP+-mediated increase in superoxide production was reduced in MAC1–/– neuron-glia cultures compared with MAC1+/+ cultures. The stunted production of superoxide in MAC1–/– microglia is likely linked to the lack of translocation of the cytosolic NADPH oxidase (PHOX) subunit (p47phox) to the membrane. In addition, the production of PGE2 markedly decreased in neuron plus MAC1–/– microglia cocultures vs neuron plus MAC1+/+ microglia cocultures. Taken together, these results demonstrate that MAC1 plays a critical role in MPTP/MPP+-induced reactive microgliosis and further support the hypothesis that reactive microgliosis is an essential step in the self-perpetuating cycle leading to progressive DAergic neurodegeneration observed in Parkinson's disease.
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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