title: Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection.
abstract: Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2(-/-) macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2(-/-) macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2(-/-) macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages.
authors: Department of Internal Medicine VI, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors: Manfred
authors: M
authors: Nairz
authors: Ulrike
authors: U
authors: Schleicher
authors: Andrea
authors: A
authors: Schroll
authors: Thomas
authors: T
authors: Sonnweber
authors: Igor
authors: I
authors: Theurl
authors: Susanne
authors: S
authors: Ludwiczek
authors: Heribert
authors: H
authors: Talasz
authors: Gerald
authors: G
authors: Brandacher
authors: Patrizia L
authors: PL
authors: Moser
authors: Martina U
authors: MU
authors: Muckenthaler
authors: Ferric C
authors: FC
authors: Fang
authors: Christian
authors: C
authors: Bogdan
authors: Günter
authors: G
authors: Weiss
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D060467:Disease Resistance; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D009569:Nitric Oxide / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014162:Transfection; D000098742:Ferroportin
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D050505:Mutant Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000098742:Ferroportin; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D007501:Iron; D052247:Nitric Oxide Synthase Type II; D003676:Deferoxamine
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