Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice
Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice
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程序性死亡-1 缺陷通过诱导小鼠小胶质细胞激活和神经炎症加重帕金森病 MPTP 模型中的运动功能障碍
DOI：
10.1007/s12035-022-02758-x
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发表时间：
2022-02-10
影响因子：
5.1
通讯作者：
Chen, Liang-Wei
中科院分区：
文献类型：
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作者：
Cheng, Ying-Ying;Chen, Bei-Yu;Chen, Liang-Wei
大量反应性神经胶质瘤和神经炎症是帕金森病（PD）患者大脑的典型病理特征，但其调节机制尚不清楚。我们对程序性死亡-1 （PD-1）在PD发病过程中神经胶质反应、神经炎症和神经元损伤中的作用感兴趣。采用PD小鼠模型和PD-1敲除（KO）小鼠，设计野生型对照（WT-CON）、wt -1-甲基-4-苯基-1,2,3,6-四氢吡啶（WT-MPTP）、PD-1-KO-对照（KO- con）和PD-1-KO- mptp (KO- mptp)，通过运动行为检测、免疫组织化学和western blot观察动物运动功能障碍、PD-1阳性细胞形态分布、多巴胺能神经元损伤、胶质细胞活化和中脑炎性细胞因子的产生。与WT-CON小鼠相比，WT-MPTP小鼠黑质中PD-1/ iba1阳性小胶质细胞减少。四组比较，PD-1缺乏使动物运动功能障碍加重，TH蛋白表达减少，TH阳性神经元突起减少。PD-1缺乏增强了MPTP模型黑质中小胶质细胞的活化，诱导型一氧化氮合酶、肿瘤坏死因子- α、白细胞介素-1 β和白细胞介素-6等促炎细胞因子的产生，以及AKT和ERK1/2的表达和磷酸化。我们认为PD-1缺乏可通过诱导中脑小胶质细胞活化和神经炎症加重MPTP小鼠模型的运动功能障碍，提示PD-1信号异常可能参与PD的发病机制。
Abundant reactive gliosis and neuroinflammation are typical pathogenetic hallmarks of brains in Parkinson's disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroinflammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1-positive cells, dopaminergic neuronal injury, glial activation and generation of inflammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 deficiency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 deficiency enhanced microglial activation, production of proinflammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.