Xue Feng, Zhang Mei, Zhao Rui-Yue, Wang Xiao-Wen, Gu Yu, Yang Ye, Chen Wen-Fang
Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
Brain Behav Immun. 2025 May;126:260-273. doi: 10.1016/j.bbi.2025.02.013. Epub 2025 Feb 18.
Neuroinflammation mediated by microglial activation plays a prominent role in the pathogenesis of Parkinson's disease (PD). Dendritic cell-associated C-type lectin-1 (Dectin-1) is a pattern recognition receptor that is involved in innate immunity. However, the role of Dectin-1 on dopaminergic neuronal damage remains unclear. Our results demonstrated that the expression of Dectin-1 was significantly increased in the microglia of the LPS-induced PD mouse model. Inhibition of Dectin-1 by laminarin (LAM) attenuated LPS-induced dopaminergic neuronal damage in substantia nigra (SN) and behavioral deficits and promoted the phenotypic transformation of microglia from M1 to M2. Moreover, inhibition or knockdown of Dectin-1 significantly decreased LPS-induced phosphorylation of Syk and P65 as well as the production of COX-2 and iNOS in BV2 cells. Knockdown of Syk also significantly decreased LPS-induced protein expressions of COX-2 and iNOS. Mechanistically, both TLR4 inhibitor and NF-κB inhibitor could antagonize LPS-induced Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays showed a physical binding of NF-κB/P65 to Dectin-1 promoter, which further indicated the regulatory effect of toll-like receptor 4 (TLR4)/NF-κB signaling pathway on Dectin-1 expression. Furthermore, the present study provided the first evidence that Dectin-1 activation by hot-alkali treated depleted zymosan (d-Zymosan) could induce dopaminergic neurotoxicity and motor dysfunction, and promote up-regulation of TLR4, iNOS and Iba-1 in C57BL/6J mice. In conclusion, Dectin-1-Syk synergistic signaling crosstalk with TLR4/NF-κB promotes and maintains inflammatory phenotypes of M1 microglia which induces dopaminergic neuronal damage in SN. These findings provide novel insights into the pivotal role of Dectin-1 in neuroinflammation, suggesting its potential as a novel therapeutic target for PD.
由小胶质细胞激活介导的神经炎症在帕金森病（PD）的发病机制中起重要作用。树突状细胞相关的C型凝集素-1（Dectin-1）是一种参与固有免疫的模式识别受体。然而，Dectin-1对多巴胺能神经元损伤的作用仍不清楚。我们的结果表明，在脂多糖（LPS）诱导的PD小鼠模型的小胶质细胞中，Dectin-1的表达显著增加。海带多糖（LAM）对Dectin-1的抑制作用减轻了LPS诱导的黑质（SN）多巴胺能神经元损伤和行为缺陷，并促进了小胶质细胞从M1型向M2型的表型转化。此外，抑制或敲低Dectin-1可显著降低LPS诱导的BV2细胞中Syk和P65的磷酸化以及COX-2和iNOS的产生。敲低Syk也显著降低了LPS诱导的COX-2和iNOS的蛋白表达。机制上，TLR4抑制剂和NF-κB抑制剂均可拮抗LPS诱导的Dectin-1表达。染色质免疫沉淀（ChIP）分析显示NF-κB/P65与Dectin-1启动子存在物理结合，这进一步表明Toll样受体4（TLR4）/NF-κB信号通路对Dectin-1表达的调节作用。此外，本研究首次证明热碱处理的脱颗粒酵母聚糖（d-Zymosan）激活Dectin-1可诱导C57BL/6J小鼠多巴胺能神经毒性和运动功能障碍，并促进TLR4、iNOS和Iba-1的上调。总之，Dectin-1-Syk协同信号与TLR4/NF-κB相互作用促进并维持M1小胶质细胞的炎症表型，从而诱导SN中的多巴胺能神经元损伤。这些发现为Dectin-1在神经炎症中的关键作用提供了新的见解，表明其作为PD新型治疗靶点的潜力。
