Despite the prevalence and recognition of its detrimental impact, clinical complications of sepsis remain a major challenge. Here, we investigated the effects of myeloid ferritin heavy chain (FtH) in regulating the pathogenic sequelae of sepsis. We demonstrate that deletion of myeloid FtH leads to tolerance towards sepsis as evidenced by reduced serum cytokine levels, multi-organ dysfunction and subsequent mortality. We identified that such tolerance is predominantly mediated by the compensatory increase in circulating ferritin (ferritin light chain; FtL) in the absence of myeloid FtH. Our in vitro and in vivo studies indicate that prior exposure to ferritin provides significant tolerance to the septic process by restraining an otherwise dysregulated response to infection. These findings are mediated by an inhibitory action of ferritin on NF-B activation and its downstream effects. Taken together, our findings suggest an essential immunomodulatory function for circulating ferritin and enhances our understanding of this acute phase reactant. SOURCE: Sooryanarayana Varambally (svarambally@uabmc.edu) -  University of Alabama

Pluto Bioinformatics

GSE114078: Transcriptome profiling of blood leukocytes from FtH LysM-/- and FtH fl/fl mice following sham or CLP surgery