Da-Qi Zhang , Ge Li , Zong-Dong Fu , Yu-Sheng Huang , Xiao-Li Feng , Li-Jun Chen , Rong Wang , Wen-Jie Zhao , Qifu Li
{"title":"鸢尾素通过抑制小胶质细胞NLRP3炎性体通路改善脂多糖诱导的神经炎症小鼠模型的认知障碍","authors":"Da-Qi Zhang , Ge Li , Zong-Dong Fu , Yu-Sheng Huang , Xiao-Li Feng , Li-Jun Chen , Rong Wang , Wen-Jie Zhao , Qifu Li","doi":"10.1016/j.neuropharm.2025.110572","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>in vivo</em> and <em>in vitro</em>. 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.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110572"},"PeriodicalIF":4.6000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Irisin ameliorates cognitive impairment in a lipopolysaccharide-induced neuroinflammation mouse model by inhibiting the NLRP3 inflammasome pathway in microglia\",\"authors\":\"Da-Qi Zhang , Ge Li , Zong-Dong Fu , Yu-Sheng Huang , Xiao-Li Feng , Li-Jun Chen , Rong Wang , Wen-Jie Zhao , Qifu Li\",\"doi\":\"10.1016/j.neuropharm.2025.110572\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>in vivo</em> and <em>in vitro</em>. 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.</div></div>\",\"PeriodicalId\":19139,\"journal\":{\"name\":\"Neuropharmacology\",\"volume\":\"278 \",\"pages\":\"Article 110572\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0028390825002783\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390825002783","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Irisin ameliorates cognitive impairment in a lipopolysaccharide-induced neuroinflammation mouse model by inhibiting the NLRP3 inflammasome pathway in microglia
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.
期刊介绍:
Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).