Yin Xi, Li Ge, Ji Fei, Wang Miao, Gao Yang, Li Fengzhu, Wang Zhenfu, Han Gencheng, Gao Zhongbao
Department of Neurology, The Second Medical Center and National Clinical Research Center for Geriatric Disease, Chinese PLA General Hospital, Beijing, China.
Department of Neuroimmune and Antibody Engineering, Beijing Institute of Basic Medical Sciences, Beijing, China.
Mol Neurobiol. 2025 May;62(5):5566-5578. doi: 10.1007/s12035-024-04560-3. Epub 2024 Nov 23.
Parkinson's disease (PD) is a common neurodegenerative disorder, and neuroinflammation plays a pivotal role in its pathogenesis. T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3) is a crucial immunoregulatory mediator in various diseases; however, its roles and underlying molecular mechanisms in PD remain unclear. We established in vitro and in vivo 1-methyl-4-phenylpyridinium (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models in Tim-3-knockout BV2 cells and mice, respectively. Motor function was assessed through behavioral tests, including pole, traction, forced swimming, and open field tests. Immunofluorescence was used to examine dopaminergic neuron loss and glial activation. The expression levels of nuclear factor-kappa B (NF-κB)/nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) pathway components were evaluated by western blotting. Proinflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA). Compared with the wild-type, Tim-3 expression was significantly increased in the PD model, and Tim-3 deficiency mitigated MPTP-induced motor deficits, dopaminergic neuron loss, and glial cell activation. Furthermore, Tim-3 deficiency suppressed neuroinflammation by negatively modulating the NF-κB/NLRP3 pathway, thereby downregulating the expression of the proinflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α. These findings indicate that Tim-3 plays a proinflammatory role in PD by regulating the NF-κB/NLRP3 pathway, highlighting Tim-3 as a promising therapeutic target for PD.
帕金森病（PD）是一种常见的神经退行性疾病，神经炎症在其发病机制中起关键作用。T细胞免疫球蛋白和粘蛋白结构域分子3（Tim-3）是各种疾病中一种关键的免疫调节介质；然而，其在帕金森病中的作用及潜在分子机制仍不清楚。我们分别在Tim-3基因敲除的BV2细胞和小鼠中建立了体外和体内1-甲基-4-苯基吡啶离子（MPP+）/1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病模型。通过行为测试评估运动功能，包括杆试验、牵引试验、强迫游泳试验和旷场试验。采用免疫荧光法检测多巴胺能神经元丢失和胶质细胞活化情况。通过蛋白质印迹法评估核因子κB（NF-κB）/核苷酸结合寡聚化结构域样受体3（NLRP3）通路成分的表达水平。通过酶联免疫吸附测定（ELISA）检测促炎细胞因子。与野生型相比，帕金森病模型中Tim-3表达显著增加，Tim-3缺乏减轻了MPTP诱导的运动功能障碍、多巴胺能神经元丢失和胶质细胞活化。此外，Tim-3缺乏通过负向调节NF-κB/NLRP3通路抑制神经炎症，从而下调促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达。这些发现表明，Tim-3通过调节NF-κB/NLRP3通路在帕金森病中发挥促炎作用，凸显了Tim-3作为帕金森病一个有前景的治疗靶点。
