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Cited by 115Iron Metabolism and DisordersImmune Response and InflammationFerroptosis and cancer prognosis

Innate Nutritional Immunity

Open access
Núñez, Gabriel, Sakamoto, Kei, Soares, Miguel P·2018·The Journal of Immunology
DOI 10.4049/jimmunol.1800325PMC PMC6028930
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Abstract

Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed “nutritional immunity.” Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.

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Crossref · 10.4049/jimmunol.1800325

Cites

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Claims the paper makes

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  • Premisecitation

    Mammals use conserved mechanisms to withhold iron from pathogens and confer resistance to infectious diseases, a strategy called nutritional immunity.

    “Several evolutionarily conserved mechanisms are operational in mammals to withhold Fe from pathogens and confer resistance to infectious diseases, a defense strategy termed nutritional immunity (10, 11).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Weinberg, 1975, Nutritional immunity. Host’s attempt to withhold iron from microbial invaders, JAMA source

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    • cites [11] Oppenheimer, 2001, Iron and its relation to immunity and infectious disease, J. Nutr. source

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  • Premisecitation

    Iron in red blood cell hemoglobin is recycled mainly by erythrophagocytic macrophages in the splenic red pulp engulfing and digesting senescent or damaged red blood cells.

    “This is circumvented by the recycling of the Fe contained in the heme groups of Hb inside RBC (14–16), achieved largely via the continuous engulfment and digestion of senescent or damaged RBC by erythrophagocytic macrophages (EM) in the red pulp of the spleen (15) (Figure 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Muckenthaler, 2017, A red carpet for iron metabolism, Cell source

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    • cites [15] Soares, 2016, Macrophages and iron metabolism, Immunity source

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    • cites [16] Ganz, 2015, Iron homeostasis in host defence and inflammation, Nat. Rev. Immunol. source

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  • Premisecitation

    Cell-autonomous and systemic mechanisms regulate cellular iron import versus export and subcellular iron localization to control iron's damaging potential.

    “This potentially damaging process is controlled via cell autonomous and systemic mechanisms that regulate the relative rate of cellular Fe import vs. export as well Fe subcellular localization (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Soares, 2015, The iron age of host–microbe interactions, EMBO Rep. source

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  • Interpretationreasoning

    These regulatory mechanisms are needed to separate iron withholding from pathogens from iron toxicity and cellular damage.

    “These regulatory mechanisms are critical to decouple Fe withholding from pathogens from Fe toxicity and cellular damage.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Microbes can acquire iron through high-affinity iron-binding molecules called siderophores.

    “This can be achieved via the expression of a variety of microbially encoded high affinity Fe-binding molecules known as siderophores (17) (Figure 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Crosa, 2002, Genetics and assembly line enzymology of siderophore biosynthesis in bacteria, Microbiol. Mol. Biol. Rev. source

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  • May combine two claims. 33
  • Classified as probably not a substantial claim. 4

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    Interpretationreasoning

    The main heme pool is in hemoglobin inside red blood cells, making red blood cells a prime target for pathogens seeking iron.

    “The major pool of heme is contained in hemoglobin (Hb) in RBC, a prime target for pathogens in search of this essential resource.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    Most pathogens evolved ways to divert host iron into their own metabolism, while hosts evolved ways to restrict pathogen iron access.

    “Presumably, this explains why most pathogens evolved a variety of strategies aimed at diverting Fe from their hosts into their own metabolic pathways, while hosts co-evolved strategies to restrict pathogens from accessing Fe (3–6).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Cassat, 2013, Iron in infection and immunity, Cell Host Microbe source

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    • cites [4] Hood, 2012, Nutritional immunity: transition metals at the pathogen–host interface, Nat. Rev. Microbiol. source

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    • cites [5] Soares, 2015, The iron age of host–microbe interactions, EMBO Rep. source

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    • cites [6] Palmer, 2016, Transition metals and virulence in bacteria, Annu. Rev. Genet. source

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    Premisecitation

    Competition for limited iron became a conserved host defense against infection in plants and animals and also a microbial virulence factor.

    “where competition for limited Fe resources emerged as an evolutionary conserved host defense strategy against infection in plants (2) and animals (3–5) as well as a microbial virulence factor (6).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Verbon, 2017, Iron and immunity, Annu. Rev. Phytopathol. source

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    • cites [3] Cassat, 2013, Iron in infection and immunity, Cell Host Microbe source

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    • cites [4] Hood, 2012, Nutritional immunity: transition metals at the pathogen–host interface, Nat. Rev. Microbiol. source

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    • cites [5] Soares, 2015, The iron age of host–microbe interactions, EMBO Rep. source

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    • cites [6] Palmer, 2016, Transition metals and virulence in bacteria, Annu. Rev. Genet. source

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

    Premisecitation

    In mammals, most iron is present as heme, a hydrophobic iron-containing tetrapyrrole that binds iron through nitrogen atoms.

    “In mammals, the large majority of Fe exists in the form of heme, a hydrophobic Fe-based compound in which four methane-bridged pyrroles form a tetrapyrrole ring that binds Fe through nitrogen atoms (7, 8).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Tsiftsoglou, 2006, Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects, Pharmacol. Ther. source

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    • cites [8] Poulos, 2007, The Janus nature of heme, Nat. Prod. Rep. source

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    Premisecitation

    Dietary iron compensates for physiologic iron loss but is insufficient for the iron demands of erythropoiesis and other homeostatic processes.

    “While sufficient to compensate for physiologic loss of Fe associated with epithelial shedding or bleeding, dietary Fe fails to match the amounts needed to support heme biosynthesis associated with erythropoiesis as well as other biologic processes sustaining homeostasis (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Muckenthaler, 2017, A red carpet for iron metabolism, Cell source

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  • May combine two claims.

    Premisecitation

    This recycling extracts heme iron and sends it to bone marrow for erythropoiesis, where iron is inserted into nascent hemoglobin.

    “This process allows for the Fe contained in the heme groups of Hb to be extracted and directed into the bone marrow to support erythropoiesis, where Fe is inserted in the last step of heme biosynthesis and incorporated into nascent Hb (15) (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Soares, 2016, Macrophages and iron metabolism, Immunity source

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    Premisecitation

    Hydroxyl radicals oxidize proteins, lipids, DNA, and organelles, causing oxidative stress and cellular damage.

    “This eventually leads to the production of hydroxyl radicals, which oxidize proteins, lipids and DNA as well as cellular organelles, leading to oxidative stress and cellular damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kumar, 2005, Free heme toxicity and its detoxification systems in human, Toxicol. Lett. source

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    Premisecitation

    Iron's biological importance comes from its ability to shift between ferrous and ferric states and act as a redox catalyst in many life-sustaining reactions.

    “The biologic importance of Fe resides in its intrinsic ability to shift between ferrous (Fe2+) and ferric (Fe3+) states, as well as higher oxidation states, via reversible exchange of electrons with electrophile or nucleophile molecules, respectively (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Chapman, 1997, Heme: the most versatile redox centre in biology?, Metal Sites in Proteins and Models source

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    Premisecitation

    FTH ferroxidase activity converts Fe2+ to Fe3+, enabling storage of up to 4500 Fe3+ atoms per ferritin complex.

    “The ferroxidase activity of FTH is critical for the conversion of Fe2+ into Fe3+, allowing the storage of 4500 Fe3+ atoms per ferritin complex (45, 46).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Gozzelino, 2014, Coupling heme and iron metabolism via ferritin H chain, Antioxid. Redox Signal. source

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    • cites [46] Harrison, 1996, The ferritins - molecular properties, iron storage function and cellular regulation

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    Premisecitation

    Hypoferremia causes iron overload in macrophages and parenchymal cells, interrupts iron supply for erythropoiesis, and leads to anemia of inflammation.

    “While conferring resistance to extracellular pathogens, hypoferremia is associated with a high evolutionary trade-off in that it leads to Fe overload in macrophages and parenchyma cells, interrupting Fe supply to support erythropoiesis, resulting in the development of anemia of inflammation (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Soares, 2015, The iron age of host–microbe interactions, EMBO Rep. source

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    Premisecitation

    Hepcidin binds ferroportin and causes its degradation, systemically blocking cellular iron efflux.

    “Hepcidin binds and triggers ferroportin degradation, inhibiting cellular Fe efflux systemically (18, 20, 21).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Nemeth, 2004, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization, Science source

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    • cites [20] Ganz, 2011, Hepcidin and disorders of iron metabolism

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    • cites [21] Rodriguez, 2014, Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6, Infect. Immun. source

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  • May combine two claims.

    Premisecitation

    Ferritin's protective effect does not involve changing host pathogen load, indicating that ferritin establishes disease tolerance to infection.

    “This protective effect is not associated with modulation of host pathogen load, revealing that ferritin establishes disease tolerance to infection (44, 54, 55).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [44] Soares, 2014, Tissue damage control in disease tolerance, Trends Immunol. source

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    • cites [54] Soares, 2017, Disease tolerance and immunity in host protection against infection, Nat. Rev. Immunol. source

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    • cites [55] Medzhitov, 2012, Disease tolerance as a defense strategy, Science source

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    Premisecitation

    Ferritin induction is essential for host survival of extracellular bacterial infections and Plasmodium infection.

    “Induction of ferritin expression is essential to sustain host survival of extracellular bacterial infections (52) as well as Plasmodium infection (53).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Weis, 2017, Metabolic adaptation establishes disease tolerance to sepsis, Cell source

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    • cites [53] Gozzelino, 2012, Metabolic adaptation to tissue iron overload confers tolerance to malaria, Cell Host Microbe source

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    Premisecitation

    Ferritin expression is induced post-transcriptionally by iron overload and transcriptionally through NF-κB activation downstream of PRR or cytokine receptors.

    “Ferritin expression is highly induced, post-transcriptionally, in response to Fe overload (48) as well as transcriptionally through the activation of the nuclear factor kappa B (NF-κB) family of transcription factors downstream of PRR or cytokine receptors (49, 50).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [48] Hentze, 1987, Identification of the iron-responsive element for the translational regulation of human ferritin mRNA, Science source

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    • cites [49] Kwak, 1995, Role for NF-κB in the regulation of ferritin H by tumor necrosis factor-α, J. Biol. Chem. source

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    • cites [50] Miller, 1991, Iron-independent induction of ferritin H chain by tumor necrosis factor, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    Lactoferrin is a transferrin-family iron-binding protein that contributes to the antimicrobial activity of breast milk.

    “Another mechanism by which innate immune responses restrain extracellular pathogens from accessing Fe, involves lactoferrin, a member of the transferrin family of Fe binding proteins that contributes to the anti-microbial activity of breast milk (28, 29).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Brocke, 2002, The human intronless melanocortin 4-receptor gene is NMD insensitive, Hum. Mol. Genet. source

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    • cites [29] Brock, 2002, The physiology of lactoferrin, Biochem. Cell Biol. source

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    Premisecitation

    HAMP transcription in hepatocytes is induced by iron, by microbial sensing through pattern recognition receptors, or by innate immune cytokines including IL-1β, IL-6, and IL-22.

    “HAMP transcription is induced in hepatocytes in response to i) Fe, ii) microbial sensing by pattern recognition receptors (PRR) or iii) cytokines produced by innate immune cells, including IL-1β, IL-6 or IL-22 (19, 22–24).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Drakesmith, 2012, Hepcidin and the iron-infection axis, Science source

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    • cites [22] Loréal, 2014, Iron, hepcidin, and the metal connection, Front. Pharmacol.

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    • cites [23] Armitage, 2011, Hepcidin regulation by innate immune and infectious stimuli, Blood source

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    • cites [24] Nemeth, 2003, Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein, Blood source

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  • May combine two claims.

    Premisecitation

    Lactoferrin is secreted by macrophages and polymorphonuclear cells at mucosal surfaces, binds Fe3+ with very high affinity, and restricts the virulence of various extracellular pathogens.

    “This glycoprotein secreted by macrophages and polymorphonuclear cells (PMN) at mucosal surfaces binds Fe3+ with high affinity (KD ∼ 10−20 M) and in doing so restricts the virulence of a variety of extracellular pathogens (29–31).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Brock, 2002, The physiology of lactoferrin, Biochem. Cell Biol. source

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    • cites [30] Nairz, 2014, Iron at the interface of immunity and infection, Front. Pharmacol. source

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    • cites [31] Kontoghiorghes, 1995, Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches, Blood Rev. source

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

    Premisecitation

    Ferritins are conserved multimeric complexes made of adjustable ratios of FTH and FTL proteins encoded by two genes.

    “Ferritins are evolutionary conserved multimeric protein complexes composed of adjustable ratios of heart/heavy chain (FTH) and liver/light chain (FTL) proteins, encoded by two distinct genes (45, 46).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Gozzelino, 2014, Coupling heme and iron metabolism via ferritin H chain, Antioxid. Redox Signal. source

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    • cites [46] Harrison, 1996, The ferritins - molecular properties, iron storage function and cellular regulation

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  • May combine two claims.

    Premisecitation

    IRPs sense intracellular iron and bind iron-responsive elements on target mRNAs including TFR1, ferritin, and ferroportin, controlling their stability.

    “IRPs sense intracellular Fe content and bind cis-regulatory iron responsive elements (IREs) on target mRNAs including TFR1, ferritin and ferroportin, regulating their stability (59).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Forbes, 2001, Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions, Trends Microbiol. source

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    Premisecitation

    Superoxide from NOX2 reacts with nitric oxide to form peroxynitrate, a stable reactive nitrogen species that is cytotoxic to pathogens and confers resistance to infections.

    “Briefly, superoxide (•O2−) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2 family member (gp91phox)(63), reacts with NO• and generates peroxinitrate (ONNO−), a stable form of reactive nitrogen species (RNS) that is cytotoxic to pathogens and confers resistance to infections (Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Yu, 1998, Gp91phox is the heme binding subunit of the superoxide-generating NADPH oxidase, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    Most bacterial pathogens secrete siderophores that bind Fe3+ with very high affinity and can recapture iron from host transferrin or lactoferrin.

    “Most bacterial pathogens secrete siderophores that bind Fe3+ at extremely high affinity and can (re)capture Fe from host Fe-binding proteins such as transferrin or lactoferrin (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Miethke, 2007, Siderophore-based iron acquisition and pathogen control, Microbiol. Mol. Biol. Rev. source

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    Premisecitation

    Extracellular hemoglobin dissociates into dimers that auto-oxidize, releasing heme and producing labile heme.

    “Extracellular Hb dissociates readily into dimers, which are prone to auto oxidation, releasing their prosthetic heme groups and generating labile heme (75, 76) (Figure 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Gouveia, 2017, Characterization of plasma labile heme in hemolytic conditions, FEBS J. source

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    • cites [76] Ferreira, 2008, A central role for free heme in the pathogenesis of severe malaria: the missing link?, J. Mol. Med. (Berl.) source

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    Premisecitation

    The general way to limit iron for intracellular pathogens is to lower intracellular Fe2+ by blocking extracellular uptake, promoting Fe3+ storage in ferritin, or increasing Fe2+ efflux.

    “The general strategy to limit Fe availability to intracellular pathogens consists in reducing intracellular Fe2+ concentration, via mechanisms i) inhibiting extracellular Fe uptake, ii) promoting Fe3+ storage in ferritin or iii) increasing cellular Fe2+ efflux (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Soares, 2015, The iron age of host–microbe interactions, EMBO Rep. source

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    Premisecitation

    Macrophages without Nramp1 activity have higher intracellular iron, which is linked to greater pathogen load in endosomes.

    “Macrophages lacking Nramp1 activity exhibit higher intracellular Fe content, which is associated with increased pathogen load in endosomes (57, 58).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Jabado, 2000, Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane, J. Exp. Med. source

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    • cites [58] Soe-Lin, 2009, Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    TonB-dependent outer membrane heme, hemoprotein, and hemophore receptors shuttle heme to the bacterial periplasm, where ABC periplasmic permeases transport it into the cytosol.

    “These are recognized by outer membrane TonB-dependent heme, hemoprotein and hemophore receptors, respectively, which shuttle heme to the bacterial periplasm to be transported into the cytosol by specific ABC protein-dependent periplasmic permeases (3, 77).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Cassat, 2013, Iron in infection and immunity, Cell Host Microbe source

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    • cites [77] Wandersman, 2000, Bacterial heme sources: the role of heme, hemoprotein receptors and hemophores, Curr. Opin. Microbiol. source

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    Premisecitation

    Reactive nitrogen species activate Nrf2, which regulates ferroportin expression, promotes cellular iron export, and lowers intracellular iron.

    “Aside from its intrinsic microbicidal activity, RNS also activate the transcription factor Nrf2, which regulates ferroportin expression, promoting Fe cellular export and reducing intracellular Fe content (64, 65).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Nairz, 2008, Interferon-γ limits the availability of iron for intramacrophage Salmonella typhimurium, Eur. J. Immunol. source

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    • cites [65] Nairz, 2013, Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection, J. Exp. Med. source

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    Premisecitation

    Hemopexin, though viewed as protective against labile heme, also acts in nutritional immunity by limiting heme availability to extracellular bacteria, as shown for Citrobacter rodentium and commensal E. coli.

    “While thought to act exclusively as part of a protective response limiting the pathogenic effects of labile heme (79, 80), hemopexin also acts as a component of nutritional immunity, limiting heme availability to extracellular bacteria, as demonstrated for Citrobacter rodentium and commensal E. coli (81).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [79] Soares, 2016, Red alert: labile heme is an alarmin, Curr. Opin. Immunol. source

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    • cites [80] Tolosano, 2010, Heme scavenging and the other facets of hemopexin, Antioxid. Redox Signal. source

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    • cites [81] Sakamoto, 2017, IL-22 controls iron-dependent nutritional immunity against systemic bacterial infections, Sci. Immunol. source

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

    Premisecitation

    Enterobactin is a prototypical siderophore produced by Enterobacteriaceae.

    “This strategy is perhaps best illustrated for Enterobactin, a prototypical siderophore produced by Enterobacteriaceae (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Miethke, 2007, Siderophore-based iron acquisition and pathogen control, Microbiol. Mol. Biol. Rev. source

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    Premisecitation

    Plasmodium spp. invade and multiply inside red blood cells and access their heme-iron content.

    “Perhaps the clearest example of such a strategy is the one co-opted by Plasmodium spp., which invade and proliferate inside RBC, accessing their heme-Fe content (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Sigala, 2014, The peculiarities and paradoxes of Plasmodium heme metabolism, Annu. Rev. Microbiol. source

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    Premisecitation

    Nramp1 lowers phagosomal iron and restricts vacuolar growth of Salmonella Typhimurium, Leishmania donovani, and Mycobacterium bovis, but not cytosolic Listeria monocytogenes.

    “Nramp1 reduces Fe concentration in phagosomes, restricting the vacuolar growth of intracellular pathogens such as Salmonella enterica serovar Typhimurium (Salmonella), Leishmania donovani and Mycobacteriun bovis, but not Listeria monocytogenes that exhibit a cytosolic life style (56–60).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [56] Vidal, 1995, The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene, J. Exp. Med. source

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    • cites [57] Jabado, 2000, Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane, J. Exp. Med. source

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    • cites [58] Soe-Lin, 2009, Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo, Proc. Natl. Acad. Sci. USA source

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    • cites [59] Forbes, 2001, Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions, Trends Microbiol. source

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    • cites [60] Haschka, 2015, Contrasting regulation of macrophage iron homeostasis in response to infection with Listeria monocytogenes depending on localization of bacteria, Metallomics source

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  • May combine two claims.

    Premisecitation

    Siderophores such as enterobactin are essential for iron acquisition by many bacterial pathogens including E. coli and Salmonella, coupled with siderophore receptor expression.

    “Siderophores such as Enterobactin are essential for Fe acquisition by many bacterial pathogens such as E. coli or Salmonella, a strategy coupled to the expression of siderophore receptors by these pathogens (85, 86).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Miethke, 2007, Siderophore-based iron acquisition and pathogen control, Microbiol. Mol. Biol. Rev. source

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    • cites [86] Hantke, 2003, Salmochelins, siderophores of Salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    Lcn2 binds siderophores such as enterobactin and delivers Lcn2-Fe-siderophore complexes to host cells through the Lcn2 receptor, blocking bacterial uptake of iron-laden siderophores.

    “Lcn2 binds siderophores such as enterobactin and delivers Lcn2-Fe-siderophore complexes to host cells via the Lcn2 receptor (88, 89), inhibiting bacterial uptake of Fe-laden siderophores (87, 90).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Flo, 2004, Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron, Nature source

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    • cites [88] Devireddy, 2010, A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production, Cell source

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    • cites [89] Bao, 2010, Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex, Nat. Chem. Biol. source

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  • May combine two claims.

    Interpretationreasoning

    Nutritional immunity must be coupled to tissue damage control mechanisms that detoxify heme-iron and help establish disease tolerance to infections.

    “This defense strategy must be coupled to tissue damage control mechanisms that detoxify heme-Fe and contribute to establishing disease tolerance to infections.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because most mammalian iron is in heme, microbial pathogens evolved to capture heme for iron, while hosts evolved to withhold heme from pathogens.

    “Given that the large majority of Fe in mammals is contained inside heme, microbial pathogens evolved to capture heme as the means to access Fe while hosts co-evolved to withhold heme from microbial pathogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    This defense strategy changes cellular iron content, which affects the microbicidal activity of innate immune cells such as macrophages.

    “Importantly, this defense strategy modulates cellular Fe content, which impacts on the microbicidal activity of innate immune cells such as macrophages (30, 98, 99).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Nairz, 2014, Iron at the interface of immunity and infection, Front. Pharmacol. source

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    • cites [98] Recalcati, 2010, Differential regulation of iron homeostasis during human macrophage polarized activation, Eur. J. Immunol. source

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    • cites [99] Recalcati, 2012, Iron levels in polarized macrophages: regulation of immunity and autoimmunity, Autoimmun. Rev. source

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

    Premisecitation

    The concept of nutritional immunity was proposed more than 40 years ago.

    “While the concept of nutritional immunity was proposed over 40 years ago (10), this defense strategy has not gained much attention among immunologists.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Weinberg, 1975, Nutritional immunity. Host’s attempt to withhold iron from microbial invaders, JAMA source

      Not checked in the free run.

36 of 36

  • The paper relies on this without support.

    Iron is essential for microbial pathogens and is required for their proliferation.

    “Fe is required to support microbial expansion and as such infection relies strictly on the capacity of pathogenic microorganisms to acquire this essential nutrient from their hosts.”

  • The paper relies on this without support.

    Each red blood cell contains about 1.2×10^9 iron molecules, and adult healthy humans carry about 2–3×10^13 red blood cells.

    “considering that each RBC contains 1.2×109 Fe molecules and that adult healthy humans carry about 2−3×1013 RBC”

  • The paper relies on this without support.

    Plasmodium spp. can synthesize heme.

    “While Plasmodium spp. can synthetize heme, Trypanosomatid protozoan parasites, such as Leishmania spp. and Trypanosoma spp. are natural heme auxotrophs that rely on host heme acquisition and transport for their survival.”

  • The paper relies on this without support.

    Leishmania spp. and Trypanosoma spp. are natural heme auxotrophs that depend on host heme acquisition and transport for survival.

    “While Plasmodium spp. can synthetize heme, Trypanosomatid protozoan parasites, such as Leishmania spp. and Trypanosoma spp. are natural heme auxotrophs that rely on host heme acquisition and transport for their survival.”

  • The paper relies on this without support.

    Bacterial pathogens use hemolysins to damage red blood cells and release hemoglobin.

    “Bacterial pathogens co-opted alternative strategies, which rely on the expression of hemolysins, damaging RBC and releasing their Hb content (Figure 2).”

  • The paper relies on this without support.

    Lcn2 is a soluble peptide secreted by activated polymorphonuclear cells, monocyte/macrophages, and epithelial cells after PRR engagement.

    “Lcn2 is a soluble peptide secreted by activated PMN, monocyte/macrophages and epithelial cells in response to the engagement of PRRs.”
6 of 6

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?

  • Iron impacts innate immune function mainly by interfering with myeloid cells.

    “Additional evidence exists that iron impacts on innate immune function mainly by interfering with myeloid cells.”

    From Iron in immune cell function and host defense (2021) · cites this paper as [138]

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Authors
Núñez, G., Sakamoto, K., & Soares, M. P.
Affiliations
  • University of Michigan (US)
  • Instituto Gulbenkian de Ciência (PT)
Corresponding author
Sakamoto, Kei
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2018-07-01
Volume
201
Issue
1
Pages
11-18
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1800325
PMC
PMC6028930
OpenAlex
W2809685970
Semantic Scholar
436804da46353b9fc5aeb368fdc8dda6abe4cfd9
Cited by
115
References
116
Citations by year
2026: 8 · 2025: 14 · 2024: 14 · 2023: 14 · 2022: 18 · 2021: 15 · 2020: 19 · 2019: 10 · 2018: 3
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095782, R01DK061707, R01DK091191)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
nutritional immunity, iron metabolism, innate immunity, host-pathogen interaction, iron limitation, host defense against infection
MeSH terms
Animals, Bacteria, Bacterial Infections, Heme, Humans, Immunity, Innate, Iron, Macrophages, Oxidation-Reduction, Mice

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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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