Dataset Information

Whole-transcriptome analysis of spleens from WT and myeloid ferritin H-deficient animals upon Salmonella infection

ABSTRACT: Iron is an essential nutrient for humans as well as for pathogens. Hence, its correct distribution at the systemic and cellular level is mandatory for mounting an effective innate immune defense. Here we delved into the role of macrophage-expressed iron storing protein ferritin H (FTH) in immune response against the model intracellular pathogen Salmonella Typhimurium. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+ Fthfl/fl) displayed impaired iron storage capacities in tissue leukocyte compartment, increased levels of labile iron in macrophages and an accelerated macrophage-mediated iron turnover. Without iron supplementation, wildtype (WT) and LysM-Cre+/+ Fthfl/fl animals showed comparable susceptibility to Salmonella infection. Interestingly, iron supplementation rapidly elicited symptoms of cytokine storm and drastically shortened survival of LysM-Cre+/+ Fthfl/fl mice. Mechanistically, we traced this phenotype back to labile iron-mediated hyperactivity of the inflammasome in FTH-deficient macrophages, culminating in excessive IL-1β secretion and secondary triggering of NF-kappaB-dependent inflammatory circuits. Accordingly, bacterial burden and cytokine levels in iron-loaded LysM-Cre+/+ Fthfl/fl mice could be effectively kept at bay by pharmacological inflammasome and IL-1β blockade. These findings point towards a previously unrecognized role of ferritin as an inhibitor of iron-dependent inflammasome activity in macrophages and a checkpoint of systemic innate response.

ORGANISM(S): Mus musculus

PROVIDER: GSE145114 | GEO | 2021/02/12

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.

Dataset Information

Whole-transcriptome analysis of spleens from WT and myeloid ferritin H-deficient animals upon Salmonella infection

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets