Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation
Open Access
- 6 July 2021
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 6 (13)
- https://doi.org/10.1172/jci.insight.141760
Abstract
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.Keywords
Funding Information
- Austrian Research Fund (P 28302)
- Austrian Research Fund (P 33062)
- Austrian Research Fund (I 3321 Epicross)
- Austrian Research Fund (W 1253 HOROS)
- Austrian Academy of Sciences (DOC stipend)
- Österreichische Krebshilfe Tirol (15024)
- Christian Doppler Research Society (AOP Orphan Pharmaceuticals AG)
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