Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation

Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre(+/+)Fth(fl/fl) mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre(+/+)Fth(+/+) and LysM-Cre(+/+)Fth(fl/fl) animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre(+/+)Fth(fl/fl) mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-kappa B and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1 beta pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-kappa B and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.

Automated summary

Iron is essential for both mammals and pathogens, and inflammation-induced changes in iron metabolism play a crucial role in host defense against infections. The iron storage protein FTH in myeloid cells is important for controlling bacterial spread and modulating NF-κB and inflammasome-mediated cytokine activation.