MYELOID-SPECIFIC FERRITIN LIGHT CHAIN DELETION DOES NOT EXACERBATE SEPSIS-ASSOCIATED AKI

Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae of 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 ferritin, an iron storage protein comprised of ferritin light (FtL) and heavy chain (FtH). 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 will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, myeloid FtL and serum ferritin levels were significantly lower in the knockout mice. Interestingly, while sepsis led to production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function and injury, identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. 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. FtL deletion did not impact 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, loss of FtL did not influence sepsis pathogenesis.