{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:17:50Z","timestamp":1791256670424,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T00:00:00Z","timestamp":1714608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J of Neuroscience"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Microglia are endogenous immune cells in the brain, and their pyroptosis and phenotype dichotomy are proved to play roles in neurodegenerative diseases. We investigated whether and how hypoxia affected pyroptosis and phenotype polarization in mouse microglia. Primary mouse microglia and BV2 microglia were exposed to hypoxia. Pyroptosis and M1\/M2 phenotype were assessed by measuring gasdermin D truncation and M1\/M2 surface marker expression. Mechanisms including purinergic ionotropic receptor (P2XR), peroxisome proliferator\u2010activated receptor coactivator\u20101\u03b1 (PGC\u20101\u03b1) and NOD\u2010like receptor protein 3 (NLRP3) inflammasome were investigated. We reported hypoxia (90% N\n                    <jats:sub>2<\/jats:sub>\n                    , 5% O\n                    <jats:sub>2<\/jats:sub>\n                    and 5% CO\n                    <jats:sub>2<\/jats:sub>\n                    ) induced pyroptosis and promoted M1 phenotype polarization in primary mouse microglia and BV2 microglia, and the effect appeared after 6\u00a0h exposure. Although hypoxia (90% N\n                    <jats:sub>2<\/jats:sub>\n                    , 5% O\n                    <jats:sub>2<\/jats:sub>\n                    and 5% CO\n                    <jats:sub>2<\/jats:sub>\n                    , 6\u00a0h) had no effect on P2X1R and P2X7R expression, it increased P2X4R expression and decreased PGC\u20101\u03b1 expression. Interestingly, blockade of P2X4R or P2X7R abolished hypoxia\u2010modulated PGC\u20101\u03b1 expression, pyroptosis and M1 polarization. PGC\u20101\u03b1 overexpression or overactivation alleviated hypoxia\u2010induced pyroptosis and M1 polarization, while PGC\u20101\u03b1 knockdown or deactivation promoted pyroptosis and M1 polarization under normoxic situation. Further, hypoxia induced NLRP3 expression and activated caspase\u20101 and induced the phosphorylation of NF\u2010\u03baB and reduced the phosphorylation of STAT3\/6. NLRP3 inhibitor and caspase\u20101 inhibitor abolished hypoxia\u2010induced pyroptosis, while NF\u2010\u03baB inhibitor and STAT phosphorylation inducer ameliorated hypoxia\u2010induced M1 polarization. In addition, NF\u2010\u03baB activator and STAT3\/6 inhibitor caused microglia M1 polarization under normoxic situation. We concluded in cultured mouse microglia, hypoxia may induce pyroptosis via P2XR\/PGC\u20101\u03b1\/NLRP3\/caspase\u20101 pathway and trigger M1 polarization through P2XR\/PGC\u20101\u03b1\/NF\u2010\u03baB\/STAT3\/6 pathway.\n                  <\/jats:p>","DOI":"10.1111\/ejn.16363","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T21:58:53Z","timestamp":1714687133000},"page":"3629-3642","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The critical role of P2XR\/PGC\u20101\u03b1 signalling pathway in hypoxia\u2010mediated pyroptosis and M1\/M2 phenotypic differentiation of mouse microglia"],"prefix":"10.1111","volume":"60","author":[{"given":"Hao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Jing'an District Central Hospital of Shanghai Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen\u2010hua","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Jing'an District Central Hospital of Shanghai Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Jing'an District Central Hospital of Shanghai Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Jing'an District Central Hospital of Shanghai Fudan University  Shanghai People's Republic of 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