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 protection against
lipopolysaccharide-induced
endotoxemia and cecal
ligation and
puncture (CLP)-induced model of
sepsis as evidenced by reduced
cytokine levels, multi-organ dysfunction and mortality. We identified that such protection 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 light chain restrains an otherwise dysregulated response to
infection. These findings are mediated by an inhibitory action of FtL on NF-κB activation, a key signaling pathway that is implicated in the pathogenesis of
sepsis. We further identified that LPS mediated activation of MAPK pathways, specifically, JNK, and ERK were also reduced with FtL pre-treatment. Taken together, our findings elucidate a crucial immunomodulatory function for circulating
ferritin that challenges the traditional view of this
protein as a mere marker of body
iron stores. Accordingly, these findings will stimulate investigations to the adaptive nature of this
protein in diverse clinical settings.