{"title":"IFN-γ 对小胶质细胞的引诱作用涉及 STAT1 介导的 NLRP3 炎性体的激活。","authors":"Haili He, Xiaomei Zhang, Hui He, Gaojie Xu, Liangyuan Li, Chengyan Yang, Yu-e Liu, Zili You, Jinqiang Zhang","doi":"10.1111/cns.70061","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Inflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial “priming”. Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Our results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and neurotrophic factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>IFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70061","citationCount":"0","resultStr":"{\"title\":\"Microglial priming by IFN-γ involves STAT1-mediated activation of the NLRP3 inflammasome\",\"authors\":\"Haili He, Xiaomei Zhang, Hui He, Gaojie Xu, Liangyuan Li, Chengyan Yang, Yu-e Liu, Zili You, Jinqiang Zhang\",\"doi\":\"10.1111/cns.70061\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Inflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial “priming”. Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Our results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and neurotrophic factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>IFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"30 10\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70061\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70061\",\"RegionNum\":1,\"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":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70061","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Microglial priming by IFN-γ involves STAT1-mediated activation of the NLRP3 inflammasome
Background
Inflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial “priming”. Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.
Methods
We examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.
Results
Our results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and neurotrophic factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.
Conclusions
IFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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