IL-1 protects from fatal systemic candidiasis in mice by inhibiting oxidative phosphorylation and hypoxia

Sofia Horn, Mareike Schmid, Ivan Berest, Federica Piattini, Jing Zhang, Katrien de Bock, Olivier Devuyst, Stellor Nlandu Khodo, Jan Kisielow and Manfred Kopf ()
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Sofia Horn: ETH Zurich
Mareike Schmid: ETH Zurich
Ivan Berest: ETH Zurich
Federica Piattini: ETH Zurich
Jing Zhang: ETH Zurich
Katrien de Bock: ETH Zurich
Olivier Devuyst: University of Zurich
Stellor Nlandu Khodo: University of Zurich
Jan Kisielow: ETH Zurich
Manfred Kopf: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 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 Il1r1-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.

Date: 2025
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DOI: 10.1038/s41467-025-57797-4

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