TLR2 deficiency is beneficial at the late phase in MPTP-induced Parkinson' disease mice
TLR2 deficiency is beneficial at the late phase in MPTP-induced Parkinson' disease mice
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DOI：
10.1016/j.lfs.2023.122171
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发表时间：
2023-10-11
期刊：
影响因子：
6.1
通讯作者：
Huang，Fang
中科院分区：
文献类型：
--
作者：
He，Yongtao;Zhao，Jiayin;Huang，Fang
帕金森氏病（PD）是一种进行性神经退行性疾病。PD的病因尚不清楚，但神经炎症被证明是一个重要的因素。toll样受体2 （TLR2）参与多种炎症细胞因子的释放。TLR2是否作为PD中DA系统损伤的中介仍不清楚。主要方法用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）亚急性治疗stlr2敲除（Tlr2−/−）和野生型（WT）小鼠。在注入MPTP后的第3、7和14天，对其行为性能进行评估，包括Pole测试、Rotarod测试、饲养测试和Wire hang测试。此外，系统分析了黑质纹状体通路中多巴胺能变性、胶质细胞活化和α-Syn表达等pd样表型。最后，对mptp处理组的肠道菌群组成进行了评估。在MPTP给药后3天和7天，stlr2缺乏对多巴胺能损伤无明显影响。相反，在注射后第14天，TLR2缺乏不仅显著减轻了Pole试验和Rotarod试验中的运动障碍和黑质纹状体多巴胺能变性，而且通过抑制TLR2/MyD88/TRAF6/NF-κB信号通路，减轻了α-Syn异常、星形胶质细胞激活和神经炎症。此外，在突变小鼠中也检测到肠道微生物群的改变。这些发现突出了tlr2通路在mptp诱导的PD小鼠模型晚期的神经保护作用。
AimsParkinson's disease (PD) is a progressive neurodegenerative disorder. The etiology of PD is still elusive but neuroinflammation is proved to be an important contributor. Toll-like receptor 2 (TLR2) involves in the release of several inflammatory cytokines. Whether TLR2 serves as a mediator contributing to the damage of DA system in PD remain unclear.Main methodsTlr2knockout (Tlr2−/−) and wild-type (WT) mice were treated with a subacute regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At 3, 7 and 14 days after MPTP injection, the behavioral performance, including the Pole test, the Rotarod test, the Rearing test and the Wire hang test was evaluated. Moreover, the PD-like phenotypes, including dopaminergic degeneration, the activation of glial cells and the α-Syn expression were systematically analyzed in the nigrostriatal pathway. Finally, the composition of gut microbiota in the MPTP-treated groups were assessed.Key findingsTLR2 deficiency had no obvious impact on the dopaminergic injury at 3 and 7 days following MPTP administration. On the contrary, at 14 days post injection, TLR2 deficiency not only significantly attenuated motor deficits in the Pole test and the Rotarod test, and the nigrostriatal dopaminergic degeneration, but also mitigated α-Syn abnormality, astrocyte activation and neuroinflammation through the suppressed TLR2/MyD88/TRAF6/NF-κB signaling pathways. Additionally, the alteration of gut microbiota was also detected in the mutant mice.SignificanceThese findings highlight the neuroprotective effect of TLR2-pathways at the late phase in the MPTP-induced PD mouse model.