中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2521-2527.doi: 10.4103/1673-5374.313057

• 原著:退行性病与再生 • 上一篇    下一篇

应激增加多巴胺能神经元中MHC-I表达诱导帕金森病的自身免疫

  

  • 出版日期:2021-12-15 发布日期:2021-05-15
  • 基金资助:
    国家自然科学基金（81671240，81560220）；江西省青年科学基金（20151BAB215014）；江西省卫生和计划生育委员（20195109）

Stress increases MHC-I expression in dopaminergic neurons and induces autoimmune activation in Parkinson’s disease

Bao-Yan Wang1, #, Yong-Yi Ye2, #, Chen Qian1, Hong-Bo Zhang1, Heng-Xu Mao1, Long-Ping Yao1, Xiang Sun1, Guo-Hui Lu3, *, Shi-Zhong Zhang1, *   

  1. 1The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; 2Department of Neurosurgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; 3Department of Neurosurgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China 
  • Online:2021-12-15 Published:2021-05-15
  • Contact: Shi-Zhong Zhang, PhD, zhangshizhong@smu.edu.cn; Guo-Hui Lu, PhD, guohui-lu@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81671240 (to SZZ), 81560220 (to GHL); the Youth Science Foundation of Jiangxi Province of China, No. 20151BAB215014 (to GHL); and Health and Family Planning Commission of Jiangxi Province of China, No. 20195109 (to GHL).

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摘要：

有研究发现，主要组织相容性复合体Ⅰ类(MHC-I)作为一种重要的抗原提呈蛋白在黑质区多巴胺能神经元中有表达，提示其可能参与帕金森病的发生与发展。然而，氧化应激诱导帕金森病发病是否通过MHC-I途径呢？实验采用PCR与Western blot法检测MPP+处理的SH-SY5Y细胞和MPTP帕金森病模型中的多巴胺能神经元MHC-I的表达，发现两种模型中均可表达MHC-I；为了检测MHC-I的表达是否能诱导细胞毒性T细胞浸润，我们利用免疫荧光染色法检测MPTP模型的小鼠黑质区细胞毒性CD8+T细胞浸润情况，发现随着MHC-I表达CD8+T细胞浸润增加；通过向MPTP模型小鼠黑质注射抑制MHC-I表达的腺病毒，随着MHC-I表达减少CD8+T细胞浸润也显著减少，并且多巴胺能神经元凋亡也随之减少；为了进一步研究氧化应激诱导MHC-I呈递的分子机制，实验使用特异性siRNA抑制了PINK1的表达，发现MPP+处理的SH-SY5Y细胞中MHC-I的呈递更多。上述数据说明，MPP+/MPTP诱导的氧化应激可触发MHC-I呈现和自身免疫激活，使多巴胺能神经元易受免疫细胞攻击导致凋亡，这可能是氧化应激诱导帕金森病发病的机制之一，而PINK1在氧化应激诱导MHC-I呈递中具有潜在神经保护作用。

https://orcid.org/0000-0001-6713-0000 (Shi-Zhong Zhang)

关键词: 抗原呈递, 自身免疫, CD8+T细胞, 多巴胺能神经元, MHC-I, 线粒体, 神经炎症, 氧化应激, 帕金森病, PINK1

Abstract: The expression of major histocompatibility complex class I (MHC-I), a key antigen-presenting protein, can be induced in dopaminergic neurons in the substantia nigra, thus indicating its possible involvement in the occurrence and development of Parkinson’s disease. However, it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway. In the present study, polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse model. The findings revealed that MHC-I was expressed in both models. To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells, immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8 (CD8)+ T cell infiltration in the substantia nigra of MPTP-treated mice. The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+ T cells. Moreover, in MPTP-induced Parkinson’s disease model mice, the genetic knockdown of endogenous MHC-I, which was caused by injecting specific adenovirus into the substantia nigra, led to a significant reduction in CD8+ T cell infiltration and alleviated dopaminergic neuronal death. To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation, the expression of PTEN-induced kinase 1 (PINK1) was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA (siRNA), and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells. Taken together, MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation, thus rendering dopaminergic neurons susceptible to immune cells and degeneration. This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease, and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation. All animal experiments were approved by the Southern Medical University Ethics Committee (No. 81802040, approved on February 25, 2018).

Key words: antigen presentation, autoimmune, CD8+ T cell, dopaminergic neuron, major histocompatibility complex class I, mitochondria, neuroinflammation, oxidative stress, Parkinson’s disease, PINK1

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