1. Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation.
- Author
-
Haschka D, Tymoszuk P, Petzer V, Hilbe R, Heeke S, Dichtl S, Skvortsov S, Demetz E, Berger S, Seifert M, Mitterstiller AM, Moser P, Bumann D, Nairz M, Theurl I, and Weiss G
- Subjects
- Animals, Immunity, Innate, Inflammasomes metabolism, Interleukin-1beta immunology, Mice, Mice, Inbred C57BL, NF-kappa B metabolism, Signal Transduction immunology, Apoferritins deficiency, Apoferritins metabolism, Disease Susceptibility metabolism, Inflammation metabolism, Inflammation microbiology, Iron immunology, Iron metabolism, Macrophages immunology, Macrophages metabolism, Macrophages microbiology, Salmonella Infections immunology, Salmonella Infections metabolism, Salmonella typhimurium immunology
- 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+/+Fthfl/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+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β 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-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
- Published
- 2021
- Full Text
- View/download PDF