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The formation of HACE is affected by both vasogenic and cytotoxic edema. The over-activated microglia potentiate the damage of blood\u2013brain barrier (BBB) and exacerbate cytotoxic edema. In light with the activation of microglia in HACE, we aimed to investigate whether the over-activated microglia were the key turning point of acute mountain sickness to HACE. In in vivo experiments, by exposing mice to hypobaric hypoxia (7000\u00a0m above sea level) to induce HACE model, we found that microglia were activated and migrated to blood vessels. Microglia depletion by PLX5622 obviously relieved brain edema. In in vitro experiments, we found that hypoxia induced cultured microglial activation, leading to the destruction of endothelial tight junction and astrocyte swelling. Up-regulated nuclear respiratory factor 1 (NRF1) accelerated pro-inflammatory factors through transcriptional regulation on nuclear factor kappa B p65 (NF-\u03baB p65) and mitochondrial transcription factor A (TFAM) in activated microglia under hypoxia. NRF1 also up-regulated phagocytosis by transcriptional regulation on caveolin-1 (CAV-1) and adaptor-related protein complex 2 subunit beta (AP2B1). The present study reveals a new mechanism in HACE: hypoxia over-activates microglia through up-regulation of NRF1, which both induces inflammatory response through transcriptionally activating NF-\u03baB p65 and TFAM, and enhances phagocytic function through up-regulation of CAV-1 and AP2B1; hypoxia-activated microglia destroy the integrity of BBB and release pro-inflammatory factors that eventually induce HACE.<\/jats:p>","DOI":"10.1093\/jmcb\/mjac036","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T18:28:30Z","timestamp":1655317710000},"source":"Crossref","is-referenced-by-count":54,"title":["NRF1-mediated microglial activation triggers high-altitude cerebral edema"],"prefix":"10.1093","volume":"14","author":[{"given":"Xueting","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guijuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baolan","family":"Wan","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangji","family":"Dong","sequence":"additional","affiliation":[{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"},{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xue","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yapeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-907X","authenticated-orcid":false,"given":"Li","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine, Nantong University , Nantong 226019, China"},{"name":"Co-Innovation Center of Neuroregeneration, Jiangsu Key Laboratory of Neuroregeneration, Nantong University , Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"2023022806393413300_","first-page":"505","article-title":"Acute altitude illness: updated prevention and treatment guidelines from the wilderness medical society","volume":"101","author":"Armstrong","year":"2020","journal-title":"Am. 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