{"title":"在神经性疼痛中，脊髓PGC-1α的激活通过ros介导的线粒体功能障碍和NLRP3炎性体之间的反馈回路调节小胶质细胞极化。","authors":"Qingling Xu, Qiulin Zhu, Guoxu Ling, Tonghong Huang, Tingting Su, Yanhua Chen, Yubo Xie, Yu Zhong","doi":"10.1016/j.brainresbull.2025.111365","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>An imbalance in microglial polarization plays an important role in the pathogenesis of neuropathic pain. PPARγ coactivator-1α (PGC-1α), a master coregulator of gene expression in mitochondrial biogenesis, is related to microglial polarization. However, the underlying mechanism involved is poorly understood.The aim of the present study was to explore the role of PGC-1α in regulating microglial polarization through a feedback loop between reactive oxygen species (ROS)-mediated mitochondrial dysfunction and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of chronic constriction injury (CCI).</p><p><strong>Methods: </strong>we quantified pain behaviour after CCI; analysed the localization of PGC-1α and the changes in the expression of CD68 (an M1 microglial marker)/IBA1 and ARG1 (an M2 microglial marker)/IBA1 in the dorsal horn (DH) via immunofluorescence. Western blotting and immunofluorescence were used to examine the expression of target proteins. Quantitative real-time PCR (qPCR) was used to investigate the mitochondrial DNA copy number (mtDNA). ROS production was measured via dihydroethidium (DHE). SOD activity and the MDA content were measured via SOD and MDA assay kits, respectively. In addition, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>The results revealed ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome activation, microglia phenotype from the M2 to the M1 phenotype in the CCI rats.Interesting, ROS-mediated mitochondrial dysfunction is one of the critical mediators of NLRP3 inflammasome activation.NLRP3 inflammasome in turn cause ROS production and mitochondrial dysfunction, suggesting for the first time a feedback loop between ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome in the neuropathic pain.The activation of PGC-1α shifts the microglial phenotype via the modulation of a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome.</p><p><strong>Conclusions: </strong>These findings indicate that activation of PGC-1α could be a potential therapeutic approach to ameliorate neuropathic pain.</p>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":" ","pages":"111365"},"PeriodicalIF":3.5000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Activation of spinal PGC-1α regulates microglial polarization through a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome in neuropathic pain.\",\"authors\":\"Qingling Xu, Qiulin Zhu, Guoxu Ling, Tonghong Huang, Tingting Su, Yanhua Chen, Yubo Xie, Yu Zhong\",\"doi\":\"10.1016/j.brainresbull.2025.111365\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>An imbalance in microglial polarization plays an important role in the pathogenesis of neuropathic pain. PPARγ coactivator-1α (PGC-1α), a master coregulator of gene expression in mitochondrial biogenesis, is related to microglial polarization. However, the underlying mechanism involved is poorly understood.The aim of the present study was to explore the role of PGC-1α in regulating microglial polarization through a feedback loop between reactive oxygen species (ROS)-mediated mitochondrial dysfunction and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of chronic constriction injury (CCI).</p><p><strong>Methods: </strong>we quantified pain behaviour after CCI; analysed the localization of PGC-1α and the changes in the expression of CD68 (an M1 microglial marker)/IBA1 and ARG1 (an M2 microglial marker)/IBA1 in the dorsal horn (DH) via immunofluorescence. Western blotting and immunofluorescence were used to examine the expression of target proteins. Quantitative real-time PCR (qPCR) was used to investigate the mitochondrial DNA copy number (mtDNA). ROS production was measured via dihydroethidium (DHE). SOD activity and the MDA content were measured via SOD and MDA assay kits, respectively. In addition, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>The results revealed ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome activation, microglia phenotype from the M2 to the M1 phenotype in the CCI rats.Interesting, ROS-mediated mitochondrial dysfunction is one of the critical mediators of NLRP3 inflammasome activation.NLRP3 inflammasome in turn cause ROS production and mitochondrial dysfunction, suggesting for the first time a feedback loop between ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome in the neuropathic pain.The activation of PGC-1α shifts the microglial phenotype via the modulation of a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome.</p><p><strong>Conclusions: </strong>These findings indicate that activation of PGC-1α could be a potential therapeutic approach to ameliorate neuropathic pain.</p>\",\"PeriodicalId\":9302,\"journal\":{\"name\":\"Brain Research Bulletin\",\"volume\":\" \",\"pages\":\"111365\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain Research Bulletin\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.brainresbull.2025.111365\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research Bulletin","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.brainresbull.2025.111365","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Activation of spinal PGC-1α regulates microglial polarization through a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome in neuropathic pain.
Background: An imbalance in microglial polarization plays an important role in the pathogenesis of neuropathic pain. PPARγ coactivator-1α (PGC-1α), a master coregulator of gene expression in mitochondrial biogenesis, is related to microglial polarization. However, the underlying mechanism involved is poorly understood.The aim of the present study was to explore the role of PGC-1α in regulating microglial polarization through a feedback loop between reactive oxygen species (ROS)-mediated mitochondrial dysfunction and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of chronic constriction injury (CCI).
Methods: we quantified pain behaviour after CCI; analysed the localization of PGC-1α and the changes in the expression of CD68 (an M1 microglial marker)/IBA1 and ARG1 (an M2 microglial marker)/IBA1 in the dorsal horn (DH) via immunofluorescence. Western blotting and immunofluorescence were used to examine the expression of target proteins. Quantitative real-time PCR (qPCR) was used to investigate the mitochondrial DNA copy number (mtDNA). ROS production was measured via dihydroethidium (DHE). SOD activity and the MDA content were measured via SOD and MDA assay kits, respectively. In addition, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA).
Results: The results revealed ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome activation, microglia phenotype from the M2 to the M1 phenotype in the CCI rats.Interesting, ROS-mediated mitochondrial dysfunction is one of the critical mediators of NLRP3 inflammasome activation.NLRP3 inflammasome in turn cause ROS production and mitochondrial dysfunction, suggesting for the first time a feedback loop between ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome in the neuropathic pain.The activation of PGC-1α shifts the microglial phenotype via the modulation of a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome.
Conclusions: These findings indicate that activation of PGC-1α could be a potential therapeutic approach to ameliorate neuropathic pain.
期刊介绍：
The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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