Wang Le, Liu Yang, Yan Shuxin, Du Tianshu, Fu Xia, Gong Xiaoli, Zhou Xinyu, Zhang Ting, Wang Xiaomin
1Department of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.
2Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China.
Aging Dis. 2020 Mar 9;11(2):254-268. doi: 10.14336/AD.2019.0615. eCollection 2020 Apr.
Microglial activation is an important contributor to the pathogenesis of Parkinson's disease (PD). Microglia are tightly and efficiently regulated by immune checkpoints, including CD200-CD200R1 and CX3CL1-CX3CR1. Understanding the involvement of these checkpoints in disease progression provides important insights into how microglial activation contributes to PD pathology. However, so far, studies have produced seemingly conflicting results. In this study, we demonstrate that CD200R1 expression is down-regulated at both early and late stage of PD model, and CX3CR1 expression is down-regulated in early stage and recovered in late stage. In primary cultured microglia, CD200R1 and CX3CR1 expressions are both directly regulated by LPS or α-synuclein, and CD200R1 expression is more sensitively regulated than CX3CR1. In addition, CD200 knockout causes an increase in proinflammatory cytokine production and microglial activation in the midbrain. Remarkably, DA neurons in the substantial nigra are degenerated in CD200 mice. Finally, activation of the CD200R with CD200Fc alleviates the neuroinflammation in microglia. Together, these results suggest that immune checkpoints play distinct functional roles in different stage of PD pathology, and the CD200-CD200R1 axis plays a significant role in nigrostriatal neuron viability and function.
小胶质细胞激活是帕金森病（PD）发病机制的重要促成因素。小胶质细胞受到免疫检查点的严格且有效调控，包括CD200 - CD200R1和CX3CL1 - CX3CR1。了解这些检查点在疾病进展中的作用，有助于深入了解小胶质细胞激活如何导致PD病理变化。然而，迄今为止，研究结果似乎相互矛盾。在本研究中，我们证明在PD模型的早期和晚期，CD200R1表达均下调，而CX3CR1表达在早期下调并在晚期恢复。在原代培养的小胶质细胞中，CD200R1和CX3CR1表达均受脂多糖或α - 突触核蛋白直接调控，且CD200R1表达比CX3CR1更敏感。此外，CD200基因敲除导致中脑促炎细胞因子产生增加和小胶质细胞激活。值得注意的是，在CD200基因敲除小鼠中，黑质中的多巴胺能神经元发生退化。最后，用CD200Fc激活CD200R可减轻小胶质细胞中的神经炎症。总之，这些结果表明免疫检查点在PD病理的不同阶段发挥不同的功能作用，且CD200 - CD200R1轴在黑质纹状体神经元的生存能力和功能中起重要作用。
