NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.
NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.
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在帕金森病模型中，nod样受体NLRC5促进神经炎症并抑制神经元存活。
DOI：
10.1186/s12974-023-02755-4
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发表时间：
2023-04-18
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
帕金森病（PD）的主要特征是黑质致密部（SNpc）多巴胺能神经元进行性变性和过度激活的小胶质细胞和星形胶质细胞介导的神经炎症。NLRC5（核苷酸结合寡聚化结构域样受体家族caspase募集结构域5）已被报道参与多种免疫疾病，但其在神经退行性疾病中的作用尚不清楚。在本研究中，我们发现NLRC5在1-甲基-4-苯基-1,2,3,6-盐酸四氢吡啶（MPTP）诱导PD小鼠的黑质纹状体轴以及暴露于不同神经毒性刺激的初级星形胶质细胞、小胶质细胞和神经元中的表达增加。在急性mptp诱导的PD模型中，NLRC5缺失显著降低了多巴胺能系统变性，改善了运动缺陷和纹状体炎症。此外，我们发现NLRC5缺失降低了原代小胶质细胞和原代星形胶质细胞中促炎基因IL-1β、IL-6、TNF-α和COX2的表达，并降低了混合胶质细胞对LPS处理的炎症反应。此外，NLRC5缺失抑制了NF-κB和MAPK信号通路的激活，增强了混合胶质细胞中AKT-GSK-3β和AMPK信号通路的激活。此外，NLRC5缺失增加了MPP+或lps刺激的混合胶质细胞条件培养基处理的原代神经元的存活率，并促进了NF-κB和AKT信号通路的激活。此外，PD患者血液中NLRC5的mRNA表达比健康人低。因此，我们认为NLRC5促进PD的神经炎症和多巴胺能变性，并可能作为神经胶质激活的标志。在线版本包含补充材料，可在10.1186/s12974-023-02755-4获得。
Parkinson’s disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1β, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT–GSK-3β and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation. The online version contains supplementary material available at 10.1186/s12974-023-02755-4.
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影响因子：
12.8
作者：
Jeon SM
通讯作者：
Jeon SM
DOI：
10.4049/jimmunol.1003111
发表时间：
2011-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Davis BK;Roberts RA;Huang MT;Willingham SB;Conti BJ;Brickey WJ;Barker BR;Kwan M;Taxman DJ;Accavitti-Loper MA;Duncan JA;Ting JP
通讯作者：
Ting JP
影响因子：
4.8
作者：
Jijon, H;Allard, B;Jobin, C
通讯作者：
Jobin, C
影响因子：
4.4
作者：
Benko, Szilvia;Magalhaes, Joao G.;Girardin, Stephen E.
通讯作者：
Girardin, Stephen E.
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.