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IL-1 protects from fatal systemic candidiasis by inhibition of oxidative phosphorylation and hypoxia [snRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE282797 | GEO | 2025/02/20

REPOSITORIES: GEO

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IL-1 protects from fatal systemic candidiasis by inhibition of oxidative phosphorylation and hypoxia [bulk RNA-Seq]

Project description: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.

2025-02-20 | GSE282796 | GEO

HDAC1 restricts fungal-induced Th17 polarization to restrain tissue damage

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HDAC1 restricts fungal-induced Th17 polarization to restrain tissue damage [Kidney RNA-seq]

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The role of IRAKM in IL-1β-treated adipocytes

Project description:Toll-like receptors/Interleukin-1 receptor (IL-1R) signaling plays an important role in High-fat diet (HFD)-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM (IL-1R-associated kinase M)-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduced HFD-induced body weight gain, increased whole body energy expenditure and improved insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induced the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuated HFD-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a novel therapeutic target for obesity.

2022-06-09 | PXD031934 | Pride

Proximal tubular epithelial specific transcriptomics of diabetic mice treated with dapagliflozin

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Lung neutrophil subsets transcriptomes in WT and CGD mouse in response to fungal PAMPs stimulation

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