The hepcidin-ferroportin axis controls the iron content of Salmonella-containing vacuoles in macrophages
Open accessAbstract
Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN). The hepatic iron-regulatory hormone hepcidin controls FPN internalization and degradation in response to bacterial infection. Salmonella typhimurium can invade macrophages and proliferate in the Salmonella-containing vacuole (SCV). Hepcidin is reported to increase the mortality of Salmonella-infected animals by increasing the bacterial load in macrophages. Here we assess the iron levels and find that hepcidin increases iron content in the cytosol but decreases it in the SCV through FPN on the SCV membrane. Loss-of-FPN from the SCV via the action of hepcidin impairs the generation of bactericidal reactive oxygen species (ROS) as the iron content decreases. We conclude that FPN is required to provide sufficient iron to the SCV, where iron serves as a cofactor for the generation of antimicrobial ROS rather than as a nutrient for Salmonella.
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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 Lim et al., 2018
FPN1 on the phagolysosome or Salmonella-containing vacuole is necessary to provide enough iron for the generation of reactive oxygen species.
“This study however found contrary to previous expectation that the role of FPN1 on the phagolysosome or the Salmonella-containing-vacuole (SCV) is necessary to provide enough iron for the generation of reactive oxygen species.”
From Iron in immune cell function and host defense (2021) · cites this paper as [162]
FPN1 pumps iron out of the phagolysosome or Salmonella-containing vacuole to deplete bacteria of iron.
“All hitherto existing evidence supports the idea that FPN1 would rather pump iron out of this compartment to deplete the bacteria of their important nutrient.”
From Iron in immune cell function and host defense (2021) · cites this paper as [162]
FPN1 localizes on the phagolysosome as well as on the cytosolic membrane.
“Recently it has been demonstrated that FPN1 is not only localized on the cytosolic membrane, but also on the phagolysosome [162].”
From Iron in immune cell function and host defense (2021) · cites this paper as [162]
FPN is found within the membranes of intracellular vesicles, including pathogen-containing phagosomes, particularly in macrophages.
“FPN is also found within the membranes of intracellular vesicles – including pathogen‐containing phagosomes, 27 particularly in macrophages.”
From The battle for iron in enteric infections (2020) · cites this paper as [27]
HAMP can induce the degradation of phagosomal membrane FPN as well as FPN in the plasma membrane.
“Recent work suggests that HAMP can induce the degradation of phagosomal membrane FPN as well as FPN in the plasma membrane. 27”
From The battle for iron in enteric infections (2020) · cites this paper as [27]
Reduced inflow of cytosolic iron decreases intra-vacuolar iron, so reducing iron-catalysed ROS production and originating a more amenable intra-phagosomal environment, which facilitates Salmonella survival and replication.
“Reduced inflow of cytosolic iron decreases intra‐vacuolar iron, so reducing iron‐catalysed ROS production and originating a more amenable intra‐phagosomal environment, which facilitates Salmonella survival and replication. 27”
From The battle for iron in enteric infections (2020) · cites this paper as [27]
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- Authors
- Lim, D., Kim, K. S., Jeong, J.-H., Marques, O., kim, H.-J., Song, M., Lee, T.-H., Kim, J. I., Choi, H.-S., Min, J.-J., Bumann, D., Muckenthaler, M. U., & Choy, H. E.
- Affiliations
- Chonnam National University (KR)
- Heidelberg University (DE)
- Gwangju Institute of Science and Technology (KR)
- University of Basel (CH)
- Corresponding author
- Choy, Hyon E.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-05-29
- Volume
- 9
- Issue
- 1
- Pages
- 2091-2091
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5974375
- OpenAlex
- W2805951721
- Cited by
- 64
- References
- 46
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 7 · 2023: 11 · 2022: 9 · 2021: 12 · 2020: 12 · 2019: 2 · 2018: 1
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Funders
- National Research Foundation
- Deutsche Forschungsgemeinschaft (SFB 1036)
- National Research Foundation of Korea (20110018305, NRF-2017R1A2A1A17069809, 2014M3A9D5A01073658, 2017R1A6A3A04006167)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- hepcidin, ferroportin, Salmonella typhimurium, Salmonella-containing vacuole, macrophages, iron regulation, iron export, reactive oxygen species, bacterial iron acquisition, host-pathogen interaction, iron cofactor
- MeSH terms
- RAW 264.7 Cells, Ferroportin, Animals, Cell Line, Female, HeLa Cells, Humans, Iron, Macrophages, Male, Mice, Inbred C57BL, Receptors, Estrogen, Salmonella Infections, Salmonella typhimurium, Tamoxifen, Vacuoles, Reactive Oxygen Species, Cation Transport Proteins, Mice, Bacterial Load, Hepcidins
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