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Cited by 70Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake

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MULERO, Victoriano, SEARLE, Susan, BLACKWELL, Jenefer M., BROCK, Jeremy H.·2002·Biochemical Journal
DOI 10.1042/bj3630089PMC PMC1222455
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Abstract

Solute carrier 11a1 (Slc11a1; formerly Nramp1; where Nramp stands for natural-resistance-associated macrophage protein) is a proton/bivalent cation antiporter that localizes to late endosomes/lysosomes and controls resistance to pathogens. In the present study the role of Slc11a1 in iron turnover is examined in macrophages transfected with Slc11a1Gly169 (wild-type) or Slc11a1Asp169 (mutant = functional null) alleles. Following direct acquisition of transferrin (Tf)-bound iron via the Tf receptor, iron uptake and release was equivalent in wild-type and mutant macrophages and was not influenced by interferon-γ/lipopolysaccharide activation. Following phagocytosis of [59Fe]Tf—anti-Tf immune complexes, iron uptake was equivalent and up-regulated similarly with activation, but intracellular distribution was markedly different. In wild-type macrophages most iron was in the soluble (60%) rather than insoluble (12%) fraction, with 28% ferritin (Ft)-bound. With activation, the soluble component increased to 82% at the expense of Ft-bound iron (< 5%). In mutant macrophages, 40–50% of iron was in insoluble form, 50–60% was soluble and < 5% was Ft-bound. Western-blot analysis confirmed failure of mutant macrophages to degrade complexes 24h after phagocytic uptake. Confocal microscopy showed that complexes were within lysosome-associated membrane protein 1-positive vesicles in wild-type and mutant macrophages at 30min and 24h, implying failure in the degradative process in mature phagosomes in mutant macrophages. NO-mediated iron release was 2.4-fold higher in activated wild-type macrophages compared with mutant macrophages. Overall, our data suggest that iron acquired by phagocytosis and degradation is retained within the phagosomal compartment in wild-type macrophages, and that NO triggers iron release by direct secretion of phagosomal contents rather than via the cytoplasm.

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  • M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which enhances antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine IL-10.

    “In contrast, M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which has been shown to enhance antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine, IL-10 (Weiss et al., 1994; Mulero et al., 2002; Fritsch”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Mulero et al., 2002

  • NRAMP1 increases production of NO and TNF in infected macrophages while reducing IL-10 secretion, indicating that modulation of intracellular iron content regulates macrophage antimicrobial effector function.

    “NRAMP1 increases the production of NO and TNF in infected Mø, whereas IL-10 secretion is reduced, arguing again that modulation of intracellular Fe content regulates Mø antimicrobial effector function [152-155].”

    From The Iron age of host–microbe interactions (2015) · cites this paper as [155]

  • NRAMP1 shifts iron between the phagolysosome and the cytoplasmic space, making the metal less available for intracellular bacteria such as Salmonella or Mycobacteria and thereby limiting their growth.

    “NRAMP1 shifts iron between the phagolysosome and the cytoplasmic space making the metal less available for intracellular bacteria such as Salmonella or Mycobacteria thereby limiting their growth”

    From Iron in immune cell function and host defense (2021) · cites this paper as [34]

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Authors
MULERO, V., SEARLE, S., BLACKWELL, J. M., & BROCK, J. H.
Affiliations
  • Department of Immunology and Bacteriology, Western Infirmary, University of Glasgow, Glasgow G11 6NT, Scotland, U.K.
  • Addenbrooke's Hospital (GB)
  • Western Infirmary (GB)
ORCID
BLACKWELL, Jenefer M.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2002-03-22
Volume
363
Issue
1
Pages
89-94
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj3630089
PMC
PMC1222455
OpenAlex
W2061129810
Cited by
70
References
31
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 4
FWCI
2.61
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (University of Western Australia) (submittedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders
Wellcome Trust (065642)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
SLC11A1, NRAMP1, iron metabolism, phagocytosis, transferrin receptor, macrophages, phagosome maturation, ferritin, iron release, nitric oxide, lysosomes, iron turnover
MeSH terms
Natural Resistance-associated Macrophage Protein 1, Alleles, Animals, Cations, Cell Line, Cytoplasm, Humans, Iron, Lysosomes, Macrophages, Mutation, Nitric Oxide, Nitrites, Phagocytosis, Endosomes, Time Factors, Transfection, Transferrin, Up-Regulation, Apoptosis, Microscopy, Confocal, Cation Transport Proteins, Mice

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