Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation
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
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
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Research Article Immunology Infectious disease

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

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Figure 5

Inhibition of the inflammasome/IL-1β pathway prevents the S. Typhimurium–induced cytokine storm in iron-loaded FthΔ/Δ mice.

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Inhibition of the inflammasome/IL-1β pathway prevents the S. Typhimurium...
FthΔ/Δ mice were i.v. administered iron isomaltoside (2 mg elementary Fe per animal) and infected 3 days later with 500 CFU GFP-expressing S. Typhimurium (STG). Mice were i.p. injected with the caspase-1 inhibitor Ac-YVAD-cmk (Casp1i, 8 mg/kg, 1 hour after infection, A–C) or the IL-1β receptor antagonist anakinra (25 mg/kg, 3 hours after infection, D–F). The treatment with Ac-YVAD-cmk or anakinra was repeated in 12-hour intervals. Control mice were administered PBS. (A) Surviving animal fractions as a function of time (n = 7 mice per group). (B) Serum levels of IL-1β, IL-6, and TNF-α measured by ELISA 20 hours after infection (Ctrl: n = 10, Casp1i: n = 7). (C) Bacterial burden of the spleen and liver determined by plating of organ lysates (Ctrl: n = 10, Casp1i: n = 7). (D) Surviving animal fractions as a function of time (n = 10 mice per group). (E) Serum levels of IL-1β, IL-6, and TNF-α measured by ELISA 20 hours after infection (n = 7 per group). (F) Bacterial burden of the spleen and liver was determined by plating of organ lysates 20 hours after infection (n = 7 per group). In A and D, data are presented as Kaplan-Meier plots. In other panels, each point denotes single animal, and bars with whiskers represent mean ± SEM. In A and D, statistical significance was assessed with Wilcoxon test. In the other panels, statistical significance was assessed with 2-tailed t test. In the plots, Wilcoxon and t test P value are indicated.