Interferon-gamma limits the availability of iron for intramacrophage Salmonella typhimurium.
In stimulating effector functions of mononuclear phagocytes, IFN-gamma is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-gamma is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-gamma on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-gamma caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-gamma exerting a super-inducing effect. This observed regulatory impact of IFN-gamma reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-alpha production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-gamma concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity.
Nairz
Manfred
M
Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Medical University Innsbruck, Anichstrasse 35, Innsbruck, Austria.
Fritsche
Gernot
G
Brunner
Peter
P
Talasz
Heribert
H
Hantke
Klaus
K
Weiss
Günter
G
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D005293:Ferritins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D064451:Hepcidins; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098742:Ferroportin
D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; C071332:Lcn2 protein, mouse; D009569:Nitric Oxide; D007371:Interferon-gamma; D005293:Ferritins; D007501:Iron; D006419:Heme Oxygenase (Decyclizing)