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Cited by 29Iron Metabolism and DisordersImmune responses and vaccinationsFerroptosis and cancer prognosis

Contrasting regulation of macrophage iron homeostasis in response to infection with Listeria monocytogenes depending on localization of bacteria

Haschka, David, Nairz, Manfred, Demetz, Egon, Wienerroither, Sebastian, Decker, Thomas, Weiss, Günter·2015·Metallomics
DOI 10.1039/c4mt00328d
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Abstract

Due to its multiple roles for the proliferation and pathogenicity of many microbes on the one hand and via modulation of immune effector functions on the other hand the control over iron homeostasis is thought to play a decisive role in the course of infections. Diversion of cellular iron traffic is considered as an important defense mechanism of macrophages to reduce metal availability for intracellular bacteria residing in the phagosome. However, evidence is lacking whether such alterations of iron homeostasis also become evident upon infection with bacteria gaining access to the cytosol like Listeria monocytogenes. Here we show that infection of macrophages with L. monocytogenes triggers the expression of the major cellular iron exporter ferroportin1 and induces cellular iron egress. As the growth of Listeria within macrophages is promoted by iron, stimulation of ferroportin1 functionality limits the availability of the metal for Listeria residing in the cytoplasm, whereas ferroportin1 degradation upon hepcidin treatment increases intracellular bacterial growth. In parallel to an increase of ferroportin1 expression, infected macrophages induce anti-microbial immune effector mechanisms such as TNFα formation or NO expression which are aggravated upon iron deficiency. These adaptive changes of iron homeostasis and immune response pathways are only found in macrophages infected with Listeria which express listeriolysin O and are therefore able to escape from the phagosome to the cytoplasm. Listeriolysin O deficient Listeria which are restricted to the phagosome are even killed by excess iron which may be based on "iron intoxification" via macrophage radical formation, because iron supplementation in that setting is paralleled by increased ROS formation. Our results indicate that ferroportin1 mediated iron export is a nutritional immune effector pathway to control infection with Listeria residing in the cytoplasm, whereas a different strategy is observed in mutant Listeria restricted to the phagosome, where iron remains in the macrophages likewise contributing to ROS mediated intoxification of bacteria.

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  • Iron excess blocks Nos2 transcription and high output formation of NO which worsens bacterial killing of iron-laden macrophages.

    “Because of its inhibitory effects on NF-IL6 and HIF-1α, iron excess blocks Nos2 transcription and the high output formation of NO which worsens bacterial killing of iron-laden macrophages [91, 164].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [91]

  • NO or NRAMP1 induce FPN1 or LCN2 expression to stimulate cellular iron export.

    “Infection with intracellular bacteria induces a cascade of effects aiming at reducing microbial intracellular iron access whereupon several molecules including NO or NRAMP1 lead to induction of FPN1 or LCN2 expression to stimulate cellular iron export [62,158] as detailed above.”

    From Iron in immune cell function and host defense (2021) · cites this paper as [158]

  • Infection with intracellular bacteria induces a cascade of effects aiming at reducing microbial intracellular iron access.

    “Infection with intracellular bacteria induces a cascade of effects aiming at reducing microbial intracellular iron access whereupon several molecules including NO or NRAMP1 lead to induction of FPN1 or LCN2 expression to stimulate cellular iron export [62,158] as detailed above.”

    From Iron in immune cell function and host defense (2021) · cites this paper as [158]

  • Our findings are unlikely to be specific for infections with S. Typhimurium but are also relevant to other iron-dependent intracellular pathogens such as Chlamydia, Legionella, Listeria, Mycobacterium, and Leishmania.

    “Moreover, our findings are unlikely to be specific for infections with S. Typhimurium but are also relevant to other iron-dependent intracellular pathogens such as Chlamydia, Legionella and Listeria (Paradkar et al., 2008; Bellmann-Weiler et al., 2010, 2013; Haschka et al., 2015), as well as Mycobacterium and Leishmania.”

    From Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection (2017) · cites this paper as Haschka et al., 2015

  • Nramp1 lowers phagosomal iron and restricts vacuolar growth of Salmonella Typhimurium, Leishmania donovani, and Mycobacterium bovis, but not cytosolic Listeria monocytogenes.

    “Nramp1 reduces Fe concentration in phagosomes, restricting the vacuolar growth of intracellular pathogens such as Salmonella enterica serovar Typhimurium (Salmonella), Leishmania donovani and Mycobacteriun bovis, but not Listeria monocytogenes that exhibit a cytosolic life style (56–60).”

    From Innate Nutritional Immunity (2018) · cites this paper as [60]

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Authors
Haschka, D., Nairz, M., Demetz, E., Wienerroither, S., Decker, T., & Weiss, G.
Affiliations
  • Innsbruck Medical University (AT)
  • University of Vienna (AT)
Corresponding author
Weiss, Günter
ORCID
Venue
Metallomics
Publisher
Oxford University Press (OUP)
Published
2015
Volume
7
Issue
6
Pages
1036-1045
ISSN
  • 1756-5901 (ISSN-L)
  • 1756-591X
DOI
10.1039/c4mt00328d
OpenAlex
W2022854968
Cited by
29
References
50
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 1
FWCI
3.39
Type
journal article
Language
en
Open access
closed
Locations
  • Metallomics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Austrian Academy of Sciences (DOC fellowship)
  • Austrian Science Fund (TRP-188)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
Listeria monocytogenes, hepcidin, listeriolysin O, phagosome escape, iron export, reactive oxygen species, TNF-α, nitric oxide, iron deficiency, nutritional immunity, bacterial iron acquisition
MeSH terms
RAW 264.7 Cells, Ferroportin, Animals, Genes, Bacterial, Homeostasis, Iron, Iron Chelating Agents, Listeriosis, Listeria monocytogenes, Macrophages, Mice, Inbred C57BL, Phagocytosis, Time Factors, Gene Expression Regulation, Bacterial, Reactive Oxygen Species, Cation Transport Proteins, Intracellular Space, Microbial Viability, Mice, Immunomodulation

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