IL-1 protects from fatal systemic candidiasis by inhibition of oxidative phosphorylation and hypoxia [snRNA-Seq]
Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat these infections, the precise mode of action remains unclear. Using global and conditional Il1r1 knockouts in mice, we found 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. In the brain, IL-1R-signaling indirectly recruits neutrophils and monocytes by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing revealed Il1r1-mediated NF-?B-activation in distinct kidney cell types. Our data reveal excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, associated with localized hypoxia at infection foci. By showing that hypoxia promotes fungal growth and pathogenicity, our data suggest 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. Overall design: Single nucleus RNA sequencing from whole kidneys, isolated from Il1r1+/- and Il1r1-/- mice, 8 hours after i.v. infection with C. albicans