The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium.
In being both, a modifier of cellular immune effector pathways and an essential nutrient for microbes, iron is a critical determinant in host-pathogen interaction. Here, we investigated the metabolic changes of macrophage iron homeostasis and immune function following the infection of RAW264.7 murine macrophages with Salmonella typhimurium. We observed an enhanced expression of the principal iron export protein, ferroportin 1, and a subsequent increase of iron efflux in Salmonella-infected phagocytes. In parallel, the expression of haem oxygenase 1 and of the siderophore-binding peptide lipocalin 2 was markedly enhanced following pathogen entry. Collectively, these modulations reduced both the cytoplasmatic labile iron and the ferritin storage iron pool within macrophages, thus restricting the acquisition of iron by intramacrophage Salmonella. Correspondingly, limitation of macrophage iron decreased microbial survival, whereas iron supplementation impaired immune response pathways in Salmonella-infected macrophages (nitric oxide formation and tumour necrosis factor-alpha production) and promoted intracellular bacterial proliferation. Our findings suggest that the enhancement of ferroportin 1-mediated iron efflux, the upregulation of the haem-degrading enzyme haem oxygenase 1 and the induction of lipocalin 2 following infection concordantly aim at withholding iron from intracellular S. typhimurium and to increase antimicrobial immune effector pathways thus limiting pathogen proliferation.
Nairz
Manfred
M
Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria.
Theurl
Igor
I
Ludwiczek
Susanne
S
Theurl
Milan
M
Mair
Sabine M
SM
Fritsche
Gernot
G
Weiss
Günter
G
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity; 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; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; C071332:Lcn2 protein, mouse; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1