Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in <i>Salmonella</i> infection

Nairz, Manfred; Schleicher, Ulrike; Schroll, Andrea; Sonnweber, Thomas; Theurl, Igor; Ludwiczek, Susanne; Talasz, Heribert; Brandacher, Gerald; Moser, Patrizia; Muckenthaler, Martina U.; Fang, Ferric C.; Bogdan, Christian; Weiss, Günter

doi:10.1084/jem.20121946

Cited by 173 publications

(176 citation statements)

References 85 publications

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“…At each time point examined, replication of the wild type in the presence of deferasirox was significantly reduced compared to the replication of bacteria in the presence of the vehicle alone (Fig. 2B), similar to results obtained by Nairz et al (41). These results demonstrate that ferric iron transport via FepB is required for replication of Salmonella in macrophages.…”

Section: Resultssupporting

confidence: 89%

The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

et al. 2013

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bMost bacterial pathogens require iron to grow and colonize host tissues. The Gram-negative bacterium Salmonella enterica serovar Typhimurium causes a natural systemic infection of mice that models acute and chronic human typhoid fever. S. Typhimurium resides in tissues within cells of the monocyte lineage, which limit pathogen access to iron, a mechanism of nutritional immunity. The primary ferric iron import system encoded by Salmonella is the siderophore ABC transporter FepBDGC. The Fep system has a known role in acute infection, but it is unclear whether ferric iron uptake or the ferric iron binding siderophores enterobactin and salmochelin are required for persistent infection. We defined the role of the Fep iron transporter and siderophores in the replication of Salmonella in macrophages and in mice that develop acute followed by persistent infections. Replication of wild-type and iron transporter mutant Salmonella strains was quantified in cultured macrophages, fecal pellets, and host tissues in mixed-and single-infection experiments. We show that deletion of fepB attenuated Salmonella replication and colonization within macrophages and mice. Additionally, the genes required to produce and transport enterobactin and salmochelin across the outer membrane receptors, fepA and iroN, are needed for colonization of all tissues examined. However, salmochelin appears to be more important than enterobactin in the colonization of the spleen and liver, both sites of dissemination. Thus, the FepBDGC ferric iron transporter and the siderophores enterobactin and salmochelin are required by Salmonella to evade nutritional immunity in macrophages and cause persistent infection in mice.

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Section: Resultssupporting

confidence: 89%

The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

et al. 2013

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“…Increased Fpn1 expression in vivo is consistent with cell culture studies demonstrating Fpn1-dependent inhibition of intracellular Salmonella growth as a potential host defense mechanism (44)(45)(46). Export of iron by cultured macrophages reduces the supply of iron for intracellular pathogens (in this case S. Typhimurium) and thereby benefits the host (21,35,47). Consistent with high Fpn1 expression at 3 weeks postinfection, liver hepcidin mRNA levels declined between 1 and 3 weeks.…”

Section: Discussionsupporting

confidence: 80%

“…Thus, Salmonella-infected mice have a particularly strong proinflammatory response at 1 week postinfection that declines but remains significantly higher than that of control mice over the subsequent 3 weeks. The high and sustained levels of IFN-␥, in particular, are consistent with the increased tissue macrophage expression of Fpn1 (16,35), resulting in iron export and loss of iron storage in the spleen and liver.…”

Section: Quantification Of Reduced Splenic Iron In Infected Micesupporting

confidence: 53%

“…4 and 5). Nitric oxide, a product of NOS2 activity, is an activator of Fpn1 expression in macrophages (35) and inhibits S. Typhimurium replication (36). Thus, increased Fpn1 expression and iron export from splenic and hepatic macrophages may cause or contribute to the decreased iron observed in these tissues upon infection with S. Typhimurium.…”

Section: Quantification Of Reduced Splenic Iron In Infected Micementioning

confidence: 99%

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Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

et al. 2015

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e 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-␥) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-␣])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.T yphoid fever is acquired upon oral ingestion of food or water contaminated with Salmonella enterica serovar Typhi or Paratyphi and remains a serious threat to public health, especially in developing countries (1). Human typhoid fever causes a broad range of clinical signs, including splenomegaly, neuropathy, and hematopathology, such as cytopenias (2), that have been modeled in laboratory mice infected with Salmonella enterica serovar Typhimurium (3). Inbred mouse strains with differing genetic backgrounds are characterized as either sensitive or resistant to S. Typhimurium. Sensitivity to the intracellular bacterial infection is caused by genetic deficiencies in the innate or adaptive immune system (4, 5). For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6-8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by periph...

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“…44 Since hepcidin deficiency is associated with iron release from macrophages, we postulate that reduced inflammatory response in both Hepc2/2 and Hfe 2/2 models may result from a reduced iron pool in the immune monocytes/ macrophages, as was recently suggested. 45,46 Hepcidin also suppressed bacterial infection by acting directly on UPEC because we observed that simple pre-incubation of CFT073 with hepcidin was sufficient to prevent UTI. Indeed, we found that hepcidin conserved bacteriostatic and bactericidal actions reminiscent of the mechanism by which defensins exert their antibacterial activity.…”

Section: The Role Of Hepcidin In Renal Host Defense Barriersmentioning

confidence: 87%

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

Houamel

Ducrot

Lefèbvre³

et al. 2016

Journal of the American Society of Nephrology

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The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc2/2) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc2/2 mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc2/2 mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion.

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Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection

Abstract: NOS2-derived nitric oxide drives ferroportin-1–mediated iron export in Salmonella-infected macrophages, thus limiting bacterial growth.

Cited by 173 publications

References 85 publications

The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

The Ferric Enterobactin Transporter Fep Is Required for Persistent Salmonella enterica Serovar Typhimurium Infection

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

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