Zhang Da-Qi, Li Ge, Fu Zong-Dong, Huang Yu-Sheng, Feng Xiao-Li, Chen Li-Jun, Wang Rong, Zhao Wen-Jie, Li Qifu
Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, China; Key Laboratory of Emergency and Trauma of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Haikou, 571199, China.
Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, China.
Neuropharmacology. 2025 Nov 1;278:110572. doi: 10.1016/j.neuropharm.2025.110572. Epub 2025 Jun 23.
Neuroinflammation is implicated in the development of neurodegenerative diseases. Irisin was first identified as an exercise-induced skeletal muscle-secreted glycosylated protein. The main physiological functions of irisin were initially thought to include the promotion of angiogenesis; improvement of oxidative metabolism; and regulation of glucose, lipid, and mitochondrial metabolism. However, despite its demonstrated neuroprotective effects in Alzheimer's disease, the precise role of irisin in neuroinflammation, particularly in lipopolysaccharide (LPS)-induced cognitive impairment, remains unclear. This study was performed to investigate the protective effects and mechanisms of irisin on LPS-induced inflammatory cognitive impairment both in vivo and in vitro. We induced cognitive impairment in mice using LPS and evaluated cognitive function by employing the Morris water maze test. Further, we used immunofluorescence staining and flow cytometry to assess microglial activation and polarization in the cortex and hippocampus, two brain regions involved in cognitive behaviors. Western blotting was used to detect the levels of proteins related to the NLRP3 signaling pathway. Furthermore, we measured tumor necrosis factor -α, interleukin (IL)-6, CCL2, IL-4 and IL-10 levels in BV2 cells using a mouse enzyme-linked immunosorbent assay kit and characterized M1 and M2 polarization using flow cytometry. Irisin administration improved learning and cognitive abilities but inhibited microglial activation and M1 polarization in LPS-treated mice. Irisin significantly decreased the expression of NLRP3 inflammasome signaling pathway molecules in LPS-treated mice. Further, irisin suppressed microglial activation and reduced the production of proinflammatory cytokines in BV2 cells. Moreover, irisin protected PC12 cells from LPS-activated BV2 microglia-induced neurotoxicity and inhibited apoptosis in PC12 cells induced by BV2 conditioned medium. Irisin mitigated inflammatory cognitive dysfunction and suppressed microglial activation and M1-type polarization by inhibiting the NLRP3 signaling pathway.
神经炎症与神经退行性疾病的发展有关。鸢尾素最初被鉴定为一种运动诱导的骨骼肌分泌的糖基化蛋白。鸢尾素的主要生理功能最初被认为包括促进血管生成；改善氧化代谢；以及调节葡萄糖、脂质和线粒体代谢。然而，尽管鸢尾素在阿尔茨海默病中已显示出神经保护作用，但其在神经炎症中的精确作用，特别是在脂多糖（LPS）诱导的认知障碍中的作用，仍不清楚。本研究旨在探讨鸢尾素在体内和体外对LPS诱导的炎症性认知障碍的保护作用及机制。我们用LPS诱导小鼠认知障碍，并通过莫里斯水迷宫试验评估认知功能。此外，我们使用免疫荧光染色和流式细胞术来评估皮质和海马体中与认知行为有关的两个脑区的小胶质细胞激活和极化。蛋白质印迹法用于检测与NLRP3信号通路相关的蛋白质水平。此外，我们使用小鼠酶联免疫吸附测定试剂盒测量BV2细胞中肿瘤坏死因子-α、白细胞介素（IL）-6、CCL2、IL-4和IL-10的水平，并使用流式细胞术对M1和M2极化进行表征。给予鸢尾素可改善LPS处理小鼠的学习和认知能力，但抑制小胶质细胞激活和M1极化。鸢尾素显著降低LPS处理小鼠中NLRP3炎性小体信号通路分子的表达。此外，鸢尾素抑制BV2细胞中的小胶质细胞激活并减少促炎细胞因子的产生。此外，鸢尾素保护PC12细胞免受LPS激活的BV2小胶质细胞诱导的神经毒性，并抑制BV2条件培养基诱导的PC12细胞凋亡。鸢尾素通过抑制NLRP3信号通路减轻炎症性认知功能障碍并抑制小胶质细胞激活和M1型极化。
