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While IL-1 is important to combat <jats:italic>C. albicans<\/jats:italic> infections, the underlying mechanisms remain unclear. Using global and conditional <jats:italic>Il1r1<\/jats:italic> knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of <jats:italic>Il1r1-<\/jats:italic>deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.<\/jats:p>","DOI":"10.1038\/s41467-025-57797-4","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T17:44:12Z","timestamp":1742233452000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["IL-1 protects from fatal systemic candidiasis in mice by inhibiting oxidative phosphorylation and hypoxia"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0420-3975","authenticated-orcid":false,"given":"Sofia","family":"Horn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7607-9163","authenticated-orcid":false,"given":"Ivan","family":"Berest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Piattini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8232-4663","authenticated-orcid":false,"given":"Katrien","family":"de Bock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3744-4767","authenticated-orcid":false,"given":"Olivier","family":"Devuyst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6676-6648","authenticated-orcid":false,"given":"Stellor","family":"Nlandu Khodo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4482-5202","authenticated-orcid":false,"given":"Jan","family":"Kisielow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-7140","authenticated-orcid":false,"given":"Manfred","family":"Kopf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"57797_CR1","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1111\/j.1365-2958.2005.04557.x","volume":"56","author":"C Fradin","year":"2005","unstructured":"Fradin, C. et al. 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