Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, Xian Tai Road, Changchun, Jilin, 130021, China.
Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin, 130021, China.
Inflammation. 2024 Feb;47(1):404-420. doi: 10.1007/s10753-023-01918-y. Epub 2023 Nov 6.
In the realm of Parkinson's disease (PD) research, NLRP3 inflammasome-mediated pyroptosis has recently garnered significant attention as a potential novel form of dopaminergic neuronal death. Our previous research revealed the activation of innate immune-related genes, such as the TLR4 signaling pathway and interferon regulatory factor 7 (IRF7), although the specific mechanism remains unclear. Our current study shed light on whether the TLR4 signaling pathway and IRF7 can affect the pyroptosis of dopaminergic nerve cells and thus participate in the pathogenesis of PD. The PD model was constructed by MPP treatment of PC12 cells or stereotactic injection of the striatum of SD rats, and the expression of genes were detected by RT-qPCR and Western Blotting. Lentivirus, siRNA and (5Z)-7-Oxozeaenol were used to validate the regulation of this pathway on pyroptosis. The expression of TLR4, TAK1, IRF7 and pyroptosis molecular markers was upregulated after MPP treatment. IRF7 could affect dopaminergic neural cells pyroptosis by targeted regulation of NLRP3. Furthermore, inhibition of the TLR4/TAK1 signaling pathway led to a decrease in the expression of both IRF7 and NLRP3, while overexpression of IRF7 reversed the reduction in pyroptosis and increase in TH expression. TLR4/TAK1/IRF7 axis can promote PD by influencing pyroptosis through NLRP3.
在帕金森病（PD）研究领域中，NLRP3 炎性小体介导的细胞焦亡最近作为一种潜在的新型多巴胺能神经元死亡形式引起了广泛关注。我们之前的研究揭示了固有免疫相关基因的激活，如 TLR4 信号通路和干扰素调节因子 7（IRF7），尽管具体机制尚不清楚。我们目前的研究阐明了 TLR4 信号通路和 IRF7 是否能够影响多巴胺能神经元的细胞焦亡，从而参与 PD 的发病机制。通过 MPP 处理 PC12 细胞或立体定向注射 SD 大鼠纹状体构建 PD 模型，通过 RT-qPCR 和 Western Blotting 检测基因的表达。使用慢病毒、siRNA 和（5Z）-7-氧杂豆杉烯醇来验证该通路对细胞焦亡的调节作用。MPP 处理后，TLR4、TAK1、IRF7 和细胞焦亡分子标志物的表达上调。IRF7 可以通过靶向调节 NLRP3 来影响多巴胺能神经细胞的细胞焦亡。此外，抑制 TLR4/TAK1 信号通路导致 IRF7 和 NLRP3 的表达均降低，而过表达 IRF7 则逆转了细胞焦亡减少和 TH 表达增加。TLR4/TAK1/IRF7 轴可以通过影响 NLRP3 来促进 PD 发生细胞焦亡。
