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Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific <jats:italic>Hif-1\u03b1<\/jats:italic> knockout mice were further employed to elucidate the regulatory role of HIF-1\u03b1 in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1\u03b1 in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1\u03b1 is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.<\/jats:p>","DOI":"10.1186\/s12974-024-03070-2","type":"journal-article","created":{"date-parts":[[2024,3,30]],"date-time":"2024-03-30T10:01:47Z","timestamp":1711792907000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Hypoxia inducible factor-1\u03b1 regulates microglial innate immune memory and the pathology of Parkinson\u2019s disease"],"prefix":"10.1186","volume":"21","author":[{"given":"Hongtian","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshuang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongtao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zishan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangchun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaolin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenye","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhe","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,30]]},"reference":[{"issue":"7","key":"3070_CR1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028035","volume":"9","author":"BN Dugger","year":"2017","unstructured":"Dugger BN, Dickson DW. 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