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Cited by 843Iron Metabolism and DisordersFerroptosis and cancer prognosisTrace Elements in Health

Iron homeostasis in host defence and inflammation

Open access
Ganz, Tomas, Nemeth, Elizabeta·2015·Nature Reviews Immunology
DOI 10.1038/nri3863PMC PMC4801113
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Abstract

Iron is an essential trace element for multicellular organisms and nearly all microorganisms. Although iron is abundant in the environment, common forms of iron are minimally soluble and therefore poorly accessible to biological organisms. Microorganisms entering a mammalian host face multiple mechanisms that further restrict their ability to obtain iron and thereby limit their pathogenicity. Iron levels also modulate host defence, as iron content in macrophages regulates their cytokine production. Here, we review recent advances that highlight the role of systemic and cellular iron-regulating mechanisms in protecting hosts from infection, emphasizing aspects that are applicable to human health and disease.

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Crossref · 10.1038/nri3863

Cites

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Claims the paper makes

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  • Interpretationreasoning

    Hepcidin-induced hypoferraemia limits the availability of non-transferrin-bound iron during infections.

    “Therefore, we propose that hepcidin-induced hypoferraemia functions to limit the availability of non-transferrin-bound iron during infections.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    The hypoferraemic response evolved to increase transferrin's capacity to bind iron released during acute infection and tissue destruction, thereby limiting non-transferrin-bound iron available to microorganisms.

    “We propose that the hypoferraemic response evolved to provide an increased capacity for transferrin to bind iron that would be released during acute infection and during the associated destruction of tissues and erythrocytes, and so limit the generation of non-transferrin-bound iron that can be readily used by many microorganisms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most microorganisms depend absolutely on exogenous iron for survival.
    • Rests on an assumption: Malarial parasites require iron at both the liver and erythrocyte stages.
  • Interpretationreasoning

    This mechanism is particularly effective against bacterial strains that lack siderophore-mediated iron uptake, such as marine Vibrio species.

    “This mechanism is particularly effective against bacterial strains that lack siderophore-mediated iron uptake (for example, marine Vibrio species).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Treatment with hepcidin agonists (minihepcidins) rescues mice infected with siderophilic bacteria by inducing hypoferraemia and redistributing iron from extracellular space into macrophages.

    “Interestingly, mice infected with siderophilic bacteria were rescued by treatment with potent hepcidin agonists (known as minihepcidins) that induced hypoferraemia. These treatments had little or no effect on iron stores but redistributed iron from the extracellular space into macrophages.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015). This study shows that hepcidin-deficient mice are rapidly killed by V. vulnificus , but mice can be saved by the administration of minihepcidin, demonstrating the protective effect of hypoferraemia. source

      Not checked in the free run.

  • Premisecitation

    Iron-targeted nutritional immunity consists of constitutive and inducible mechanisms that deny iron to invading pathogens and thereby limit their harm to the host.

    “This led to the concept of iron-targeted nutritional immunity as a set of constitutive and inducible mechanisms that deny iron to invading pathogens and thereby limit their ability to harm the host1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Weinberg, E. D. Nutritional immunity: host's attempt to withhold iron from microbial invaders. JAMA 231, 39–41 (1975). source

      Not checked in the free run.

  • May combine two claims. 36
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Susceptibility to death from V. vulnificus infection correlates with the presence of non-transferrin-bound iron in mouse sera and with the ability of those sera to support rapid in vitro growth of V. vulnificus.

    “Susceptibility to death from infection with V. vulnificus correlated with the presence of non-transferrin-bound iron in the mouse sera and with the ability of sera from these mice to support rapid in vitro growth of V. vulnificus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015). This study shows that hepcidin-deficient mice are rapidly killed by V. vulnificus , but mice can be saved by the administration of minihepcidin, demonstrating the protective effect of hypoferraemia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infection and inflammation induce hepcidin production, which lowers plasma iron by inhibiting iron absorption and promoting iron sequestration in macrophages.

    “Infection and inflammation induce hepcidin production, driving a decrease in plasma iron concentrations by inhibiting the absorption of iron and promoting the sequestration of iron in macrophages.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Nicolas, G. et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037–1044 (2002). source

      Not checked in the free run.

    • cites [27] Goodnough, L. T., Nemeth, E. & Ganz, T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 116, 4754–4761 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactic acid bacteria have little or no requirement for iron and thrive in the iron-poor environment of the human intestine, but may be displaced by other microorganisms when iron is administered.

    “Lactic acid bacteria (also known as Lactobacillales) are normal components of the intestinal flora and have little or no requirement for iron; they thrive in the relatively iron-poor environment of the human intestine, but they may be displaced by other microorganisms when iron is administered60.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Bailey, J. R., Probert, C. S. & Cogan, T. A. Identification and characterisation of an iron-responsive candidate probiotic. PLoS ONE 6, e26507 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    The role of IREBPs in host defence and inflammation is minor, or the two IREBPs have mostly overlapping functions.

    “However, the local and systemic responses to aseptic inflammation in vivo are preserved in the absence of either of the two IREBPs3, which suggests that the role of the IREBPs in host defence and inflammation is minor or that the two IREBPs have mostly overlapping functions, an issue that needs to be examined further.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Viatte, L., Grone, H. J., Hentze, M. W. & Galy, B. In vivo role(s) of the iron regulatory proteins (IRP) 1 and 2 in aseptic local inflammation. J. Mol. Med. 87, 913–921 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Non-transferrin-bound iron can amplify tissue injury by catalysing extracellular ROS production or by being rapidly taken up by some cell types, causing cellular iron overload and secondary ROS generation.

    “Moreover, non-transferrin-bound iron can amplify tissue injury either because it catalyses the extracellular production of injurious reactive oxygen species (ROS) or because it is rapidly taken up some cell types, causing cellular iron overload with the secondary generation of ROS.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Malarial parasites require iron at both the liver and erythrocyte stages.

  • May combine two claims.

    Interpretationcitation

    This mechanism may prevent superinfection by additional malaria parasites during subsequent exposures and provides innate immune protection in infants and children without adaptive immunity.

    “This mechanism may function to prevent superinfection by additional malaria parasites during subsequent exposures to malaria-bearing mosquitoes, and it provides a form of innate immune protection in infants and children who have not yet developed an adaptive immune response to malarial parasites31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Portugal, S. et al. Host-mediated regulation of superinfection in malaria. Nat. Med. 17, 732–737 (2011). In pre-immune children, malaria parasitaemia induces hepcidin expression and redistributes iron from hepatocytes to macrophages, thereby interfering with the hepatic stage of superinfection by another malarial strain. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Tissue iron overload and resulting toxicity is proportional to the severity and duration of hepcidin deficiency, and results in progressive damage to the liver, endocrine glands and cardiac myocytes.

    “Tissue iron overload and resulting toxicity is proportional to the severity and duration of hepcidin deficiency, and results in progressive iron-mediated damage to the liver, endocrine glands and cardiac myocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most bacterial and some viral infections (influenza, HIV) rapidly increase hepcidin production in humans and mouse models, whereas hepatitis B and C virus infections fail to elicit systemic inflammatory responses and hepcidin production.

    “Interestingly, although most bacterial and some viral infections (such as influenza virus and HIV) rapidly increase hepcidin production in humans and mouse models, hepatitis B and hepatitis C virus infections fail to elicit systemic inflammatory responses and hepcidin production30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Armitage, A. E. et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections. Proc. Natl Acad. Sci. USA 111, 12187–12192 (2014). This study shows that not all infections induce hepcidin: no induction of hepcidin or hypoferraemia was observed during the viraemic phase of hepatitis B or hepatitis C virus infection. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Hepcidin is the main iron-regulatory hormone acting on ferroportin to modulate iron absorption and systemic iron distribution.

    “The role of hepcidin as the iron-regulatory hormone that acts on ferroportin to modulate iron absorption and systemic iron distribution is now well accepted, but the strong connection between hepcidin and host defence is less well appreciated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Iron depletion of macrophages could mimic hypoxia by stabilizing HIF1α and promoting transcription and synthesis of IL-1β and perhaps other cytokines.

    “Iron depletion of macrophages could therefore mimic the effects of hypoxia, stabilizing HIF1α and promoting the transcription and synthesis of IL-1β68 and perhaps other cytokines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Peyssonnaux, C. et al. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Malaria infection causes inflammation and increases hepcidin levels, redistributing iron to macrophages and away from hepatocytes that support the initial stage of infection.

    “Malaria infection causes inflammation and increases hepcidin levels, redistributing iron to macrophages and, in the long term, away from hepatocytes that normally support the initial stage of infection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Hepcidin has direct antimicrobial activity in vitro, but the concentrations and conditions required seem outside the physiological range.

    “Also similar to defensins, hepcidin has direct antimicrobial activity in vitro, but the concentrations and conditions required for this activity seem to be outside of the physiological range.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In ex vivo erythrocytes from iron-deficient donors, P. falciparum invades fewer cells and grows more slowly intracellularly than in erythrocytes from iron-replete donors.

    “In ex vivo erythrocytes from iron-deficient donors, the malarial parasite Plasmodium falciparum invades fewer cells and shows slower intracellular growth than in erythrocytes from iron-replete donors66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Clark, M. A. et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat. Commun. 5, 4446 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1β mediates systemic inflammation and activates important host defence mechanisms.

    “IL-1β mediates systemic inflammation and activates important host defence mechanisms69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Horino, T. et al. Interleukin-1-deficient mice exhibit high sensitivity to gut-derived sepsis caused by Pseudomonas aeruginosa. Cytokine 30, 339–346 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous hepcidin is protective against renal ischaemia-reperfusion injury and oxidative stress, and hepcidin deficiency exacerbates these forms of injury.

    “Indeed, a recent study showed that exogenous hepcidin is protective against renal ischaemia–reperfusion injury and oxidative stress, and that hepcidin deficiency exacerbates these forms of injury32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Scindia, Y. et al. Hepcidin mitigates renal ischemia–reperfusion injury by modulating systemic iron homeostasis. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2014101037 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some but not all studies found altered composition of intestinal flora and increased inflammation in children treated to prevent or reverse iron deficiency.

    “Motivated to understand the connection between iron supplementation and diarrhoeal illness in African children, some but not all studies found an altered composition of the intestinal flora and increased inflammation in children who were treated to prevent or reverse iron deficiency61–63.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Zimmermann, M. B. et al. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am. J. Clin. Nutr. 92, 1406–1415 (2010). source

      Not checked in the free run.

    • cites [62] Jaeggi, T. et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 64, 731–742 (2015). source

      Not checked in the free run.

    • cites [63] Dostal, A. et al. Effects of iron supplementation on dominant bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised, placebo-controlled intervention trial in South African children. Br. J. Nutr. 112, 547–556 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erythroferrone is produced by erythroblasts in response to erythropoietic stimulation and suppresses hepcidin synthesis, making more iron available for erythropoiesis.

    “Another set of regulatory factors conveys the iron requirements for erythropoiesis and includes the recently identified hormone erythroferrone12, which is produced by erythroblasts in response to erythropoietic stimulation by endogenous or synthetic erythropoietin. Erythroferrone suppresses hepcidin synthesis, making more iron available for enhanced erythropoiesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Hepcidin causes iron sequestration in macrophages and would be expected to have an anti-inflammatory effect.

    “Although the induction of IL-1β is not primarily modulated by hepcidin, hepcidin causes iron sequestration in macrophages (FIG. 3) and would be expected to have an anti-inflammatory effect67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Pagani, A. et al. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood 118, 736–746 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Cellular iron overload increases ROS production, causing cellular injury.

    “Cellular iron overload increases the production of ROS, causing cellular injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infections with intracellular microorganisms that reside in macrophages may be enhanced by hepcidin-induced iron sequestration, and hepcidin deficiency in mouse models of hereditary haemochromatosis may inhibit growth of macrophage-resident bacteria including M. tuberculosis and S. Typhimurium.

    “Paradoxically, studies in mouse models have shown that infections with intracellular microorganisms that reside in macrophages may be enhanced by hepcidin-induced iron sequestration, and conversely, hepcidin deficiency in mouse models of hereditary haemochromatosis may inhibit the growth of macrophage-resident bacteria, including Mycobacteria tuberculosis53 or Salmonella enterica serovar enterica”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Olakanmi, O., Schlesinger, L. S. & Britigan, B. E. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J. Leukoc. Biol. 81, 195–204 (2007). source

      Not checked in the free run.

    • cites [54] Nairz, M. et al. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2. Blood 114, 3642–3651 (2009). References 53 and 54 raise the possibility that hepcidin deficiency, while promoting certain extracellular infections, may be protective against intracellular pathogens. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking hepcidin fail to develop hypoferraemia after inflammatory stimulation, may have increased serum iron during infection/inflammation, and have milder anaemia of inflammation.

    “Mice engineered to lack hepcidin fail to develop hypoferraemia after inflammatory stimulation, their serum iron concentrations may even increase during infection or inflammation, and their anaemia of inflammation is milder28,29.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Kim, A. et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 123, 1129–1136 (2014). source

      Not checked in the free run.

    • cites [29] Gardenghi, S. et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 123, 1137–1145 (2014). References 28 and 29 show that IL-6 and hepcidin are important but not exclusive mediators of anaemia of inflammation in a mouse model of severe anaemia induced by heat-killed bacteria. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anaemia due to ineffective erythropoiesis, as in β-thalassaemia, is associated with severe iron overload even without transfusions, but is exacerbated by repeated transfusions.

    “Anaemia owing to ineffective erythropoiesis, as occurs most prominently in patients with β-thalassaemia, is associated with severe iron overload that develops even in the absence of blood transfusions but is exacerbated in patients who receive repeated transfusions36,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Musallam, K. M., Cappellini, M. D. & Taher, A. T. Iron overload in β-thalassemia intermedia: an emerging concern. Curr. Opin. Hematol. 20, 187–192 (2013). source

      Not checked in the free run.

    • cites [37] Maggio, A. et al. Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials. Blood Cells Mol. Dis. 47, 166–175 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    NRAMP1 likely transports iron from phagosomes and other microorganism-containing vacuoles to macrophage cytoplasm, thereby starving vacuolar microorganisms of iron.

    “most studies suggest that NRAMP1 transports iron from phagosomes and other vacuoles that contain microorganisms to the cytoplasm of macrophages76–78, thereby starving vacuolar microorganisms of iron.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [76] Soe-Lin, S. et al. Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc. Natl Acad. Sci. USA 106, 5960–5965 (2009). source

      Not checked in the free run.

    • cites [77] Cellier, M. F., Courville, P. & Campion, C. Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect. 9, 1662–1670 (2007). source

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    • cites [78] Forbes, J. R. & Gros, P. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102, 1884–1892 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The response to S. Typhimurium requires both IL-6 and ESRRγ.

    “S. Typhimurium elicits this response by a mechanism that is dependent on IL-6 and oestrogen-related receptor-γ (ESRRγ)88.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Kim, D. K. et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat. Med. 20, 419–424 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Such macrophages supply bacteria with iron obtained through erythrophagocytosis and create an M2-like setting with weakened antimicrobial activity, which helps the bacteria survive.

    “In this way, these macrophages provide the bacteria with a source of iron from erythrophagocytosis and an M2 macrophage environment with attenuated antimicrobial mechanisms favouring the survival of the bacteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IFNγ raises NRAMP1 levels, and iron export from phagosomes by NRAMP1 might partially offset systemic hepcidin.

    “NRAMP1 expression is also stimulated by IFNγ72, and NRAMP1-mediated iron export from phagosomes containing intracellular microorganisms may help to counter the effect of systemic hepcidin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Canonne-Hergaux, F., Gruenheid, S., Govoni, G. & Gros, P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc. Assoc. Am. Physicians 111, 283–289 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    To work, an iron chelator must be safe, bind ferric iron more strongly than bacterial siderophores do, and escape recognition by microbial siderophore transporters.

    “An effective iron chelator must be nontoxic, must have higher affinity for ferric iron than bacterial siderophores and must not be recognized by microbial siderophore transporters94.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Zhou, T., Ma, Y., Kong, X. & Hider, R. C. Design of iron chelators with therapeutic application. Dalton Trans. 41, 6371–6389 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Iron deficiency is widespread in developing countries and is a major cause of chronic illness and loss of economic productivity.

    “Iron deficiency is widespread in developing countries and is a major cause of chronic illness and loss of economic productivity56.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Pasricha, S. R., Drakesmith, H., Black, J., Hipgrave, D. & Biggs, B. A. Control of iron deficiency anemia in low- and middle-income countries. Blood 121, 2607–2617 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neisseria species take up transferrin only from hominids, a specificity that helps them live in humans and some other hominids.

    “The uptake of transferrin by Neisseria species is specific to hominid transferrin, indicating that this specialized uptake mechanism facilitates their residence in the human host and several other hominids83.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Noinaj, N. et al. Structural basis for iron piracy by pathogenic Neisseria. Nature 483, 53–58 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These mice still become hypoferraemic, which suggests the nitric oxide effect is local and needs intracellular bacteria, so hepcidin remains the main regulator in most iron-recycling macrophages.

    “Nevertheless, these mice develop hypoferraemia, indicating that the nitric oxide-dependent mechanism operates at a local level and requires the presence of bacteria within the macrophage, leaving most iron-recycling macrophages under the dominant regulatory influence of hepcidin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that model, mini-hepcidins quickly lowered iron in plasma and extracellular fluid, reducing non-transferrin-bound iron, which probably feeds siderophilic bacteria.

    “In this model, mini-hepcidins rapidly decreased iron concentrations in the plasma and extracellular fluid, and thereby decreased the concentrations of non-transferrin-bound iron, which is a likely source of iron for siderophilic bacteria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015). This study shows that hepcidin-deficient mice are rapidly killed by V. vulnificus , but mice can be saved by the administration of minihepcidin, demonstrating the protective effect of hypoferraemia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During chronic S. Typhimurium infection, the bacteria might trigger erythrophagocytosis and shift liver and spleen macrophages toward an M2 phenotype; host signals are also needed, but the molecular details are unknown.

    “In chronic infection with S. Typhimurium, the bacteria may induce erythrophagocytosis and the conversion of hepatic and splenic macrophages into an M2 phenotype, a process that also requires host signals but has not been characterized in molecular detail93.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Pilonieta, M. C., Moreland, S. M., English, C. N. & Detweiler, C. S. Salmonella enterica infection stimulates macrophages to hemophagocytose. mBio 5, e02211 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    During intracellular infections, the hepcidin-ferroportin axis appears harmful, yet local mechanisms in infected macrophages might offset systemic hepcidin.

    “Although the hepcidin–ferroportin system seems to function maladaptively during infections with intracellular microorganisms, this host response could be mitigated in infected macrophages by local mechanisms that counteract the systemic effects of hepcidin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most microbial infections raise IL-6 early; IL-6 then drives hepcidin transcription through JAK2-STAT3, requiring STAT3-binding sites in the HAMP promoter.

    “IL-6 is increased early in most microbial infections and it stimulates hepcidin transcription via the JAK2–STAT3 pathway in a manner dependent on STAT3-binding motifs in the promoter of HAMP (the hepcidin gene)89–91.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [89] Wrighting, D. M. & Andrews, N. C. Interleukin-6 induces hepcidin expression through STAT3. Blood 108, 3204–3209 (2006). source

      Not checked in the free run.

    • cites [90] Fleming, R. E. Hepcidin activation during inflammation: make it STAT. Gastroenterology 132, 447–449 (2007). source

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    • cites [91] Pietrangelo, A. et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132, 294–300 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite decades of work, three approved drugs for iron overload, and in vitro microbistatic evidence for some compounds, no chelator is yet used as an antimicrobial therapy.

    “Despite several decades of research in this area that have yielded three successful drugs for the treatment of iron overload disorders, and evidence of in vitro microbistatic activity for several compounds95, no chelator has yet been adopted as an antimicrobial therapeutic.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Thompson, M. G., Corey, B. W., Si, Y., Craft, D. W. & Zurawski, D. V. Antibacterial activities of iron chelators against common nosocomial pathogens. Antimicrob. Agents Chemother. 56, 5419–5421 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A direct hepcidin-mediated anti-inflammatory effect mediated by ferroportin and the JAK-STAT pathway was proposed, but JAK-STAT-mediated signalling by ferroportin was not confirmed in subsequent more-detailed studies.

    “A direct hepcidin-mediated anti-inflammatory effect mediated by ferroportin and the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway was proposed70, but JAK–STAT-mediated signalling by ferroportin was not confirmed in subsequent more-detailed studies71.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] De Domenico, I. et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J. Clin. Invest. 120, 2395–2405 (2010). source

      Not checked in the free run.

    • cites [71] Ross, S. L. et al. Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell Metab. 15, 905–917 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In infected mice, blocking the ESRRγ pathway lowered bacterial burden significantly and improved survival modestly.

    “Chemical inhibition of the ESRRγ pathway in a mouse model significantly decreased bacterial burden and modestly improved the survival of infected mice88.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Kim, D. K. et al. Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat. Med. 20, 419–424 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Since most microbes rely heavily on iron, this dependence justifies developing new antimicrobials aimed at their iron uptake systems.

    “Finally, the exquisite dependence of most microorganisms on iron provides a rationale for the design of new antimicrobials that target iron uptake mechanisms in pathogenic microorganisms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most microorganisms depend exquisitely on iron.
38 of 38

  • The paper relies on this without support.

    Most microorganisms depend absolutely on exogenous iron for survival.

    “Given the absolute dependence of most microorganisms on exogenous iron for their survival, it has been assumed that the hypoferraemia of infection and inflammation has a host defence function.”

  • The paper relies on this without support.

    Iron is essential for nearly all microorganisms.

    “Iron is also essential for nearly all microorganisms, plants and invertebrate animals, in which it functions as a catalytic component of enzymes that mediate many redox reactions that are crucial for energy production and intermediary metabolism.”

  • The paper relies on this without support.

    Non-transferrin-bound iron can amplify tissue injury by catalysing extracellular ROS production or by rapid cellular uptake causing iron overload and secondary ROS.

    “Moreover, non-transferrin-bound iron can amplify tissue injury either because it catalyses the extracellular production of injurious reactive oxygen species (ROS) or because it is rapidly taken up some cell types, causing cellular iron overload with the secondary generation of ROS.”

  • The paper relies on this without support.

    Malarial parasites require iron at both the liver and erythrocyte stages.

    “The parasites require iron at both the liver and the erythrocyte stage.”

  • The paper relies on this without support.

    Iron deficiency is endemic in tropical regions.

    “The possibility that iron deficiency, which is endemic in tropical regions, may be protective against certain infections has also been raised.”

  • The paper relies on this without support.

    Hepcidin acts on ferroportin to shift iron into macrophages.

    “In addition to hepcidin — the effects of which on ferroportin cause redistribution of iron into macrophages —”

  • The paper relies on this without support.

    Lactoferrin, unlike transferrin, keeps binding iron at the low pH found in inflamed and infected tissues.

    “Lactoferrin is a homologue of the iron carrier protein transferrin but differs from transferrin by continuing to bind iron even at low pH, which is common in inflamed and infected tissues.”

  • The paper relies on this without support.

    Siderocalin binds iron only when it is complexed with small natural organic chelators.

    “Siderocalin, a member of a family of proteins that contain a pocket (calyx) for small mostly hydrophobic molecules, binds iron when it is complexed with small natural organic chelators.”

  • The paper relies on this without support.

    Haptoglobin and haemopexin carry free haemoglobin and haem, respectively, to macrophages and hepatocytes for degradation.

    “Haptoglobin and haemopexin are carrier proteins that transport free haemoglobin and haem, respectively, for degradation by macrophages and hepatocytes.”

  • The paper relies on this without support.

    NRAMP1 is a ferrous iron transporter located in phagocytic vacuole membranes of macrophages and neutrophils.

    “NRAMP1 is a ferrous iron transporter found in the membranes of phagocytic vacuoles of macrophages and neutrophils.”

  • The paper relies on this without support.

    Red blood cells are by far the richest source of iron.

    “Erythrocytes are by far the richest source of iron”

  • The paper relies on this without support.

    Most microorganisms depend exquisitely on iron.

    “the exquisite dependence of most microorganisms on iron”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Limiting iron availability to invading pathogens is essential, as both bacterial and fungal pathogens have been shown to target haem, hemoglobin, and other iron-complex proteins.

    “This is essential in limiting iron availability to invading pathogens, as both bacterial and fungal pathogens have been shown to target haem, hemoglobin, and other iron-complex proteins (Ganz and Nemeth, 2015).”

    From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Ganz and Nemeth, 2015

    The Conclusions and perspectives section says host defences restrict microbial access to iron. The Microbial countermeasures section says pathogenic Gram-negative bacteria obtain iron from haemoglobin and other iron-containing human proteins. Our copy does not establish that fungal pathogens target those proteins, or specifically identify haem as a target. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Iron in the human host is largely unavailable as it is constantly sequestered by specialized proteins which prevent attack by ROS or exploitation by pathogens.

    “Iron in the human host is largely unavailable as it is constantly sequestered by specialized proteins which prevent attack by ROS or exploitation by pathogens (Ganz and Nemeth, 2015).”

    From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Ganz and Nemeth, 2015

  • Systemic iron levels are tightly regulated by hepcidin (encoded by HAMP), while individual cells may independently regulate iron by receptor-mediated endocytosis of transferrin.

    “Systemic iron levels are tightly regulated by iron metabolism master regulator, hepcidin (encoded by HAMP), while individual cells may independently regulate iron by receptor-mediated endocytosis of transferrin (Ganz and Nemeth, 2015).”

    From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Ganz and Nemeth, 2015

  • In the adaptive immune system, iron is an essential growth factor for the clonal expansion of lymphocyte subsets.

    “In the adaptive immune system, iron is an essential growth-factor for the clonal expansion of lymphocyte subsets (Ganz and Nemeth, 2015;Soares and Weiss, 2015;Weiss, 2002).”

    From Iron in infection and immunity (2020) · cites this paper as Ganz and Nemeth, 2015

    The Abstract says iron is essential for vertebrates generally, but does not address its role in lymphocyte expansion. Searches for lymphocytes, adaptive immunity, and clonal expansion found no passage supporting the specific claim; the paper’s discussion of clonal selection concerns microorganisms. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Iron trafficking is controlled by cytokines and acute phase proteins, whereas iron promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism.

    “Accordingly, iron trafficking is controlled by cytokines and acute phase proteins, whereas the metal itself promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism, as we will discuss later (Ganz and Nemeth, 2015; Soares and Weiss, 2015).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Ganz and Nemeth, 2015

Cites

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Related

Authors
Ganz, T., & Nemeth, E.
Affiliations
  • University of California, Los Angeles (US)
  • University of California System (US)
Corresponding author
Ganz, Tomas
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2015-07-10
Volume
15
Issue
8
Pages
500-510
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/nri3863
PMC
PMC4801113
OpenAlex
W1570067866
Cited by
843
References
100
Citations by year
2026: 89 · 2025: 78 · 2024: 90 · 2023: 75 · 2022: 103 · 2021: 81 · 2020: 82 · 2019: 63 · 2018: 69 · 2017: 58 · 2016: 47 · 2015: 7
FWCI
9.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • CYTED Ciencia y Tecnología para el Desarrollo
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107309)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
iron homeostasis, nutritional immunity, host defense, inflammation, iron limitation, infection, macrophages, cytokine production
MeSH terms
Animals, Bacterial Infections, Gene Expression Regulation, Homeostasis, Humans, Immunity, Innate, Inflammation, Iron, Macrophages, Signal Transduction, Cytokines, Nonheme Iron Proteins, Iron-Binding Proteins, Iron-Regulatory Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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