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Cited by 182Iron Metabolism and DisordersBacterial Genetics and BiotechnologySalmonella and Campylobacter epidemiology

The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium

Nairz, Manfred, Theurl, Igor, Ludwiczek, Susanne, Theurl, Milan, Mair, Sabine M., Fritsche, Gernot, Weiss, Günter·2007·Cellular Microbiology
DOI 10.1111/j.1462-5822.2007.00942.x
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Abstract

In being both, a modifier of cellular immune effector pathways and an essential nutrient for microbes, iron is a critical determinant in host-pathogen interaction. Here, we investigated the metabolic changes of macrophage iron homeostasis and immune function following the infection of RAW264.7 murine macrophages with Salmonella typhimurium. We observed an enhanced expression of the principal iron export protein, ferroportin 1, and a subsequent increase of iron efflux in Salmonella-infected phagocytes. In parallel, the expression of haem oxygenase 1 and of the siderophore-binding peptide lipocalin 2 was markedly enhanced following pathogen entry. Collectively, these modulations reduced both the cytoplasmatic labile iron and the ferritin storage iron pool within macrophages, thus restricting the acquisition of iron by intramacrophage Salmonella. Correspondingly, limitation of macrophage iron decreased microbial survival, whereas iron supplementation impaired immune response pathways in Salmonella-infected macrophages (nitric oxide formation and tumour necrosis factor-alpha production) and promoted intracellular bacterial proliferation. Our findings suggest that the enhancement of ferroportin 1-mediated iron efflux, the upregulation of the haem-degrading enzyme haem oxygenase 1 and the induction of lipocalin 2 following infection concordantly aim at withholding iron from intracellular S. typhimurium and to increase antimicrobial immune effector pathways thus limiting pathogen proliferation.

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Crossref · 10.1111/j.1462-5822.2007.00942.x

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  • Macrophages loaded with iron lose their ability to clear infections with intracellular pathogens, such as Salmonella, Mycobacteria, Chlamydia, Candida, or Legionella.

    “Thus, macrophages loaded with iron lose their ability to clear infections with intracellular pathogens, such as Salmonella, Mycobacteria, Chlamydia, Candida, or Legionella (Mencacci et al., 1997; Chlosta et al., 2006; Nairz et al., 2007; Paradkar et al., 2008; Botella et al., 2012; Bellmann-Weiler et al., 2013) whereas reduction of iron levels or addition of iron chelators can improve infection”

    From Iron at the interface of immunity and infection (2014) · cites this paper as Nairz et al., 2007

  • Infected macrophages respond by increasing Fpn1 and lipocalin 2 expression, which limits NTS replication.

    “To counteract the iron scavenging of the pathogen, infected macrophages respond by increasing Fpn1 and lipocalin 2 expression, which effectively limits NTS replication (Nairz et al., 2007).”

    From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Nairz et al., 2007

  • NRAMP1 acts as a transporter for divalent metals, including iron, and promotes iron export from the phagolysosome and then from the cytoplasm by induction of FPN expression.

    “NRAMP1 acts as a transporter for divalent metals, including iron, and promotes iron export from the phagolyosome and then from the cytoplasm by induction of FPN expression (Nairz et al., 2007; Lim et al., 2018).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2007

  • S.Tm survives inside MPS cells such as spleen and liver macrophages, causes systemic disease in mice, and is known to require iron.

    “This Gram-negative bacterium persists within MPS cells, including spleen and liver macrophages, it causes systemic disease in mice (Vazquez-Torres et al., 1999, 2004), and its dependence on iron is well established (Nairz et al., 2007).”

    From Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection (2015) · cites this paper as Nairz et al., 2007

  • Hypoferremia can be detrimental against intracellular pathogens, enhancing their growth and proliferation, as illustrated for Chlamydia, Legionella, Salmonella, and Mycobacteria.

    “However, this strategy can be detrimental against intracellular pathogens, enhancing their growth and proliferation, as illustrated for bacteria from Chlamydia, Legionella, Salmonella, and Mycobacteria spp.[98][99][100][101][102].”

    From The Iron age of host–microbe interactions (2015) · cites this paper as [100]

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Authors
Nairz, M., Theurl, I., Ludwiczek, S., Theurl, M., Mair, S. M., Fritsche, G., & Weiss, G.
Affiliations
Innsbruck Medical University (AT)
Corresponding author
Weiss, Günter
ORCID
Venue
Cellular Microbiology
Publisher
Hindawi Limited
Published
2007-09
Volume
9
Issue
9
Pages
2126-2140
ISSN
  • 1462-5814 (ISSN-L)
  • 1462-5822
DOI
10.1111/j.1462-5822.2007.00942.x
OpenAlex
W2086904281
Cited by
182
References
63
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 13 · 2017: 8 · 2016: 6 · 2015: 10 · 2014: 12 · 2013: 17 · 2012: 10
FWCI
9.16
Type
journal article
Language
en
Open access
closed
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2922 d)
Locations
  • Cellular Microbiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Austrian Science Fund
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
Keywords
iron homeostasis, macrophages, Salmonella typhimurium, ferroportin 1, heme oxygenase-1, neutrophil gelatinase-associated lipocalin, siderophores, ferritin, iron efflux, host-pathogen interaction, nitric oxide, TNF-α, intracellular bacterial survival, RAW 264.7 macrophages
MeSH terms
Lipocalin-2, Ferroportin, Acute-Phase Proteins, Animals, Cells, Cultured, Ferritins, Homeostasis, Iron, Macrophages, Phagocytes, Salmonella typhimurium, Tumor Necrosis Factor-alpha, Oncogene Proteins, Antimicrobial Cationic Peptides, Cation Transport Proteins, Mice, Heme Oxygenase-1, Lipocalins, Hepcidins

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