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-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.
Johnson
Erin E
EE
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Sandgren
Andreas
A
Cherayil
Bobby J
BJ
Murray
Megan
M
Wessling-Resnick
Marianne
M
D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D007111:Immunity, Cellular / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000502:physiology; D016133:Polymerase Chain Reaction; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D000098742:Ferroportin
D027682:Cation Transport Proteins; D016328:NF-kappa B; D000098742:Ferroportin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase