Role of Ferroportin in Macrophage-Mediated Immunity

Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I-like protein that interacts with transferrin receptors. HFE-as...

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Bibliographic Details
Published in:Infection and Immunity 2010-12, Vol.78 (12), p.5099-5106
Main Authors: Johnson, Erin E, Sandgren, Andreas, Cherayil, Bobby J, Murray, Megan, Wessling-Resnick, Marianne
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Western
Cation Transport Proteins - immunology
Cation Transport Proteins - physiology
Cell Line
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - physiology
Host Response and Inflammation
Immunity, Cellular - immunology
Immunity, Cellular - physiology
Macrophages - immunology
Macrophages - physiology
Mice
Microbiology
Mycobacterium tuberculosis
Mycobacterium tuberculosis - immunology
NF-kappa B - physiology
Nitric Oxide - biosynthesis
Nitric Oxide - physiology
Nitric Oxide Synthase - biosynthesis
Nitric Oxide Synthase - physiology
Polymerase Chain Reaction
Tuberculosis - immunology
Tuberculosis - microbiology
Tuberculosis - physiopathology
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Summary:Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I-like protein that interacts with transferrin receptors. HFE-associated hemochromatosis is characterized by abnormally high levels of the iron efflux protein ferroportin. In this study, J774 murine macrophages overexpressing ferroportin were used to investigate the influence of iron metabolism on the release of nitric oxide (NO) in response to infection. Overexpression of ferroportin significantly impaired intracellular Mycobacterium tuberculosis growth during early stages of infection. When challenged with lipopolysaccharide (LPS) or M. tuberculosis infection, control macrophages increased NO synthesis, but macrophages overexpressing ferroportin had significantly impaired NO production in response to LPS or M. tuberculosis. Increased NO synthesis in control cells was accompanied by increased iNOS mRNA and protein, while upregulation of iNOS protein was markedly reduced when J744 cells overexpressing ferroportin were challenged with LPS or M. tuberculosis, thus limiting the bactericidal activity of these macrophages. The proinflammatory cytokine gamma interferon reversed the inhibitory effect of ferroportin overexpression on NO production. These results suggest a novel role for ferroportin in attenuating macrophage-mediated immune responses.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00498-10