Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Nairz, Manfred; Fritsche, Gernot; Brunner, Peter; Talasz, Heribert; Hantke, Klaus; Weiss, Günter

doi:10.1002/eji.200738056

Cited by 151Iron Metabolism and DisordersSalmonella and Campylobacter epidemiologyImmune Response and Inflammation

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

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Nairz, Manfred, Fritsche, Gernot, Brunner, Peter, Talasz, Heribert, Hantke, Klaus, Weiss, Günter·2008·European Journal of Immunology

DOI 10.1002/eji.200738056

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Abstract

In stimulating effector functions of mononuclear phagocytes, IFN‐γ is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN‐γ is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN‐γ on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella‐infected phagocytes, IFN‐γ caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore‐capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN‐γ exerting a super‐inducing effect. This observed regulatory impact of IFN‐γ reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF‐α production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN‐γ concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. See accompanying commentary http://dx.doi.org/10.1002/eji.200838505

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IFN-γ further stimulates macrophage iron egress by the ferroportin pathway and reduces iron availability for intracellular bacteria.
“In addition, IFN-γ further stimulates MO iron egress by this pathway and reduces the iron availability for intracellular bacteria (184).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [184]
Macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron largely because iron directly inhibits the binding activities of NF-IL6 and HIF-1α.
“Specifically, macrophage functions driven by IFN-γ are impaired when macrophages are exposed to surplus iron [138, 162, 176] largely because iron directly inhibits the binding activities of the transcription factors nuclear factor interleukin-6 (NF-IL6) and hypoxia-inducible factor (HIF)-1α [55, 153] [176].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [162]
IFNγ receptor signaling induces FPN expression while inhibiting transferrin receptor-mediated iron uptake and inducing Lcn2 expression in macrophages.
“Finally, signaling via the IFNc receptor also induces FPN expression while inhibiting extracellular Fe uptake via the transferrin receptor [169] and inducing Lcn2 expression [135] in Mø (Fig 3).”
From The Iron age of host–microbe interactions (2015) · cites this paper as [169]
IFN-γ and IL-12 support the strategy of reducing microbial intracellular iron access.
“This strategy is supported by the action of several cytokines, most prominently by IFN-γ and IL-12 [159,160].”
From Iron in immune cell function and host defense (2021) · cites this paper as [159]
Reactive nitrogen species activate Nrf2, which regulates ferroportin expression, promotes cellular iron export, and lowers intracellular iron.
“Aside from its intrinsic microbicidal activity, RNS also activate the transcription factor Nrf2, which regulates ferroportin expression, promoting Fe cellular export and reducing intracellular Fe content (64, 65).”
From Innate Nutritional Immunity (2018) · cites this paper as [64]

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Authors: Nairz, M., Fritsche, G., Brunner, P., Talasz, H., Hantke, K., & Weiss, G.
Affiliations: Innsbruck Medical University (AT)
Universität Innsbruck (AT)
University of Tübingen (DE)
Corresponding author: Weiss, Günter
ORCID: Nairz, Manfred
Fritsche, Gernot
Talasz, Heribert
Hantke, Klaus
Weiss, Günter
Venue: European Journal of Immunology
Publisher: Wiley
Published: 2008-06-25
Volume: 38
Issue: 7
Pages: 1923-1936
ISSN: 0014-2980 (ISSN-L)
1521-4141
DOI: 10.1002/eji.200738056
OpenAlex: W1994035821
Cited by: 151
References: 69
Citations by year: 2026: 2 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 10 · 2017: 10 · 2016: 3 · 2015: 9 · 2014: 15 · 2013: 11 · 2012: 9
FWCI: 8.05
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: European Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: interferon-gamma, Salmonella typhimurium, iron homeostasis, macrophages, transferrin receptor 1, ferroportin 1, heme oxygenase-1, neutrophil gelatinase-associated lipocalin, nitric oxide, TNF-α, nutritional immunity
MeSH terms: Lipocalin-2, Ferroportin, Acute-Phase Proteins, Animals, Cell Line, Ferritins, Heme Oxygenase (Decyclizing), Interferon-gamma, Iron, Macrophages, Nitric Oxide, Salmonella typhimurium, Transferrin, Tumor Necrosis Factor-alpha, Oncogene Proteins, Antimicrobial Cationic Peptides, Cation Transport Proteins, Mice, Lipocalins, Hepcidins

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Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

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