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However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long\u2010term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of\n                    <jats:italic>NR4a<\/jats:italic>\n                    family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte\u2010derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD\u2010fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD\u2010induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD\u2010induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.15252\/embr.202357164","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T16:16:09Z","timestamp":1700064969000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Trained immunity induced by high\u2010salt diet impedes stroke recovery"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0662-2535","authenticated-orcid":false,"given":"Tze\u2010Yen","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3682-5912","authenticated-orcid":false,"given":"Danye","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2665-3646","authenticated-orcid":false,"given":"Wan\u2010Ru","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhih Syuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1102-125X","authenticated-orcid":false,"given":"Xin\u2010Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Hung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-8045","authenticated-orcid":false,"given":"Chia\u2010Lang","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3913-5338","authenticated-orcid":false,"given":"Liang\u2010Chuan","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7156-0510","authenticated-orcid":false,"given":"Ping\u2010Hung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9128-9166","authenticated-orcid":false,"given":"Kai\u2010Chien","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-1680","authenticated-orcid":false,"given":"Lauren H","family":"Sansing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3211-1739","authenticated-orcid":false,"given":"Che\u2010Feng","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"key":"BFEMBR202357164_CR1","first-page":"1","volume":"7","author":"S Amara","year":"2016","unstructured":"Amara S, Whalen M, Tiriveedhi V (2016) High salt induces anti\u2010inflammatory MPhi2\u2010like phenotype in peripheral macrophages. 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