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

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.

• Authors: David Haschka, Piotr Tymoszuk, Verena Petzer, Richard Hilbe, Simon Heeke, Stefanie Dichtl, Sergej Skvortsov, Egon Demetz, Sylvia Berger, Markus Seifert, Anna-Maria Mitterstiller, Patrizia Moser, Dirk Bumann, Manfred Nairz, Igor Theurl, Guenter Weiss
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 13 (07 08 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 34236052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammasomes
• Interleukin-1beta
• NF-kappa B
• Apoferritins
• Iron

Topics

• Animals
• Apoferritins (deficiency, metabolism)
• Disease Susceptibility (metabolism)
• Immunity, Innate
• Inflammasomes (metabolism)
• Inflammation (metabolism, microbiology)
• Interleukin-1beta (immunology)
• Iron (immunology, metabolism)
• Macrophages (immunology, metabolism, microbiology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Salmonella Infections (immunology, metabolism)
• Salmonella typhimurium (immunology)
• Signal Transduction (immunology)