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Cited by 57Immune Response and InflammationIron Metabolism and DisordersImmune cells in cancer

Nramp1‐functionality increases iNOS expression via repression of IL‐10 formation

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Fritsche, Gernot, Nairz, Manfred, Werner, Ernst R., Barton, Howard C., Weiss, Günter·2008·European Journal of Immunology
DOI 10.1002/eji.200838449
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Abstract

In mice, resistance to certain intracellular microbes depends on the expression of a late phagosomal protein termed natural‐resistance associated macrophage protein 1 (Nramp1, Slc11a1). Nramp1‐functionality is associated with alterations of cellular iron homeostasis and a sustained pro‐inflammatory immune response, including the formation of the antimicrobial effector molecule NO. To investigate the underlying mechanism we used RAW‐264.7 murine macrophage cells stably transfected with a functional Nramp1 allele (RAW‐37) or Nramp1 non‐functional controls (RAW‐21). We found that the production of and signalling by the anti‐inflammatory cytokine IL‐10 was significantly enhanced in macrophages lacking functional Nramp1. Upon infection of macrophages with Salmonella typhimurium pathogen survival was significantly better in RAW‐21 than in RAW‐37, which inversely correlated to NO and TNF‐α formation. Addition of a neutralising anti‐IL‐10 antibody to RAW‐21 cells led to a significantly reduced survival of S. typhimurium within these cells and enhanced formation of NO and TNF‐α reaching levels comparable to that observed in cells bearing functional Nramp1. Oppositely, supplementation of iron to RAW‐21 cells further increased IL‐10 formation. Thus, Nramp1 mediates effective host defence in part via suppression of excessive IL‐10 production which may relate to Nramp1‐mediated reduction of cellular iron pools, thus strengthening antimicrobial effector mechanisms.

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Crossref · 10.1002/eji.200838449

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  • Iron excess stimulates formation of the macrophage de-activating cytokine IL-10.

    “Mechanistically, the latter observation can be referred to the fact that iron exerts inhibitory effects toward IFN-γ-mediated immune pathways such as the formation of TNF-α, IL-6, IL-12 MHC class II, of IDO or NOS2 (185, 187–189), whereas iron excess stimulates the formation of the macrophage de-activating cytokine IL-10 (190).”

    From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [190]

  • Nramp1-mediated alterations of iron homeostasis stimulate anti-microbial immune effector function in murine macrophages, reflected by increased NO or TNF-α and significantly reduced IL-10.

    “In addition, Nramp1-mediated alterations of iron homeostasis stimulate anti-microbial immune effector function in murine macrophages as reflected by increased formation of NO or TNF-α whereas the expression of the anti-inflammatory cytokine IL-10 is significantly reduced (167, 190).”

    From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [190]

  • 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 Fritsche et al., 2008

  • 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 [153]

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Authors
Fritsche, G., Nairz, M., Werner, E. R., Barton, H. C., & Weiss, G.
Affiliations
  • Innsbruck Medical University (AT)
  • University of Southampton (GB)
Corresponding author
Weiss, Günter
ORCID
Venue
European Journal of Immunology
Publisher
Wiley
Published
2008-11
Volume
38
Issue
11
Pages
3060-3067
ISSN
  • 0014-2980 (ISSN-L)
  • 1521-4141
DOI
10.1002/eji.200838449
OpenAlex
W2123672726
Cited by
57
References
48
Citations by year
2026: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 5
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 6 d)
Locations
  • European Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
Funders
Austrian Science Fund
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
NRAMP1, SLC11A1, IL-10, nitric oxide, inducible nitric oxide synthase, macrophages, Salmonella typhimurium, iron homeostasis, TNF-α, anti-inflammatory cytokines, host defense, phagocytosis, RAW 264.7 macrophages
MeSH terms
Natural Resistance-associated Macrophage Protein 1, Animals, Cells, Cultured, Mice, Inbred BALB C, Nitric Oxide, Tumor Necrosis Factor-alpha, Interleukin-10, Cation Transport Proteins, STAT3 Transcription Factor, Mice, Nitric Oxide Synthase Type II

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