title: Increased ferroportin-1 expression and rapid splenic iron loss occur with anemia caused by Salmonella enterica Serovar Typhimurium infection in mice.
abstract: The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-γ) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-α]) and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection.
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA Center for Comparative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA dbrown31@mgh.harvard.edu detweile@colorado.edu.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Brown
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Nick
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Melissa W
authors.initials: MW
authors.lastname: McCoy
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Moreland
authors.affiliation: Center for Comparative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Stepanek
authors.affiliation: Premier Laboratories, Boulder, Colorado, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Benik
authors.affiliation: Department of Medical Oncology, Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Karyn E
authors.initials: KE
authors.lastname: O'Connell
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pilonieta
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA.
authors.forename: Toni A
authors.initials: TA
authors.lastname: Nagy
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, USA dbrown31@mgh.harvard.edu detweile@colorado.edu.
authors.forename: Corrella S
authors.initials: CS
authors.lastname: Detweiler
mesh_terms: D000740:Anemia / Q000209:etiology*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism; D005260:Female; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000150:complications / Q000378:metabolism*; D012486:Salmonella typhimurium; D013154:Spleen; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D000098742:Ferroportin; D007501:Iron
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