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Cited by 183Iron Metabolism and DisordersIron and Steelmaking ProcessesFerroptosis and cancer prognosis

“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels

Open access
Nairz, Manfred, Theurl, Igor, Swirski, Filip K., Weiss, Guenter·2017·Pflügers Archiv - European Journal of Physiology
DOI 10.1007/s00424-017-1944-8PMC PMC5362662
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Abstract

Macrophages reside in virtually every organ. First arising during embryogenesis, macrophages replenish themselves in the adult through a combination of self-renewal and influx of bone marrow-derived monocytes. As large phagocytic cells, macrophages participate in innate immunity while contributing to tissue-specific homeostatic functions. Among the key metabolic tasks are senescent red blood cell recycling, free heme detoxification, and provision of iron for de novo hemoglobin synthesis. While this systemic mechanism involves the shuttling of iron between spleen, liver, and bone marrow through the concerted function of defined macrophage populations, similar circuits appear to exist within the microenvironment of other organs. The high turnover of iron is the prerequisite for continuous erythropoiesis and tissue integrity but challenges macrophages' ability to maintain cellular iron homeostasis and immune function.This review provides a brief overview of systemic, microenvironmental, and cellular aspects of macrophage iron handling with a focus on exciting and unresolved questions in the field.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes how macrophages handle iron at systemic, microenvironmental, and cellular levels, emphasizing red blood cell recycling, the hepcidin–ferroportin axis, and local iron circuits in organs such as liver, spleen, muscle, heart, vessels, brain, retina, bone, and bone marrow. It argues that macrophage iron homeostasis is central to erythropoiesis, tissue integrity, and immunity, while many mechanistic questions remain unresolved.

Key findings

  • Systemic iron homeostasis depends on macrophage recycling of senescent red blood cells: 20–25 mg/day of iron is needed for new RBC production, dietary absorption supplies only 1–2 mg/day, the adult Hb iron pool is 1500–2500 mg, RBC lifespan averages 120 days, and splenic red pulp macrophages clear more than 2 × 10⁶ RBC per second in a healthy adult.
  • The hepcidin–ferroportin-1 (Fpn1) axis is central: hepatocyte-derived hepcidin targets Fpn1 for degradation, reducing iron transfer from macrophages and the diet into plasma; macrophage iron handling is further controlled by Bach1/Nrf2, SpiC, HIFs, IRPs, Hmox1, Flvcr, and Nramp1.
  • Local iron-recycling circuits exist beyond the spleen and liver: liver Kupffer cells dominate clearance during excessive RBC damage and recruit CCR2⁺ monocytes via CCL2/CCL3; muscle injury involves myoglobin (17 kDa, below the kidney’s 30–50 kDa filtration cutoff); and analogous macrophage iron handling is discussed in heart, atherosclerotic plaques, brain microglia, retina, osteoclasts, and bone marrow erythroid islands.
  • Macrophage iron overload impairs antimicrobial immunity: iron inhibits NF-IL6 and HIF-1α binding, blocks Nos2/NO formation, and promotes ROS/NF-κB, while IRP1/IRP2 deletion impairs control of Salmonella Typhimurium.

Methods

  • Narrative review; no primary experiments, systematic search strategy, or meta-analysis are described.
  • Synthesizes published literature and includes a table of selected macrophage iron-handling proteins and figures on systemic and cellular iron pathways.
  • Main analysis is conceptual and mechanistic synthesis across systemic, organ-level, and cellular contexts.

Limitations

  • Stated: many unresolved questions remain, including mechanistic insight into atherosclerosis, brain iron handling, and iron shuttling from erythroid island macrophages to erythroblasts; findings from small animal models need translation to humans.
  • Stated: some areas are controversial, such as the role of Kupffer cells in hepcidin regulation and the directionality of Nramp1 iron transport.
  • Evident: as a narrative review, it lacks systematic inclusion criteria and primary data, so conclusions depend on selected cited literature and may reflect selection bias.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00424-017-1944-8

Cites

267 of 267 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 158 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    When the capacity of red pulp macrophages and Kupffer cells is overwhelmed, the cells die, presumably by ferroptosis induced by iron-mediated oxidative stress and lipid peroxidation.

    “However, when the capacity of red pulp macrophages (the iron-recycling macrophage population in the spleen, henceforward abbreviated as RPM) and KC is overwhelmed, the cells die, presumably by a specific form of cell death called ferroptosis that is induced by iron-mediated oxidative stress and lipid peroxidation [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072 source

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  • Premisecitation

    Degradation of Bach1 induces expression of SpiC independently of Nrf2.

    “Second, the degradation of Bach1 induces expression of the transcription factor (an E26 transformation-specific transcription factor of the Spi subfamily) SpiC independently of Nrf2 [116, 211].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Kohyama M, Ise W, Edelson BT, Wilker PR, Hildner K, Mejia C, Frazier WA, Murphy TL, Murphy KM (2009) Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318–321 source

      Not checked in the free run.

    • cites [211] Soares MP, Hamza I (2016) Macrophages and iron metabolism. Immunity 44:492–504 source

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  • Interpretationreasoning

    Maintenance of iron homeostasis at the systemic level requires iron recycling, much of which is contained in senescent red blood cells.

    “The maintenance of iron homeostasis at the systemic level requires iron recycling (Fig. 1), much of which is contained in senescent red blood cells (RBC).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Monocyte recruitment from the bone marrow to the liver is mediated by a liver-specific, Kupffer cell-derived CC-chemokine gradient of CCL2 and CCL3 that attracts CCR2+ CCR5+ monocytes.

    “Indeed, monocyte recruitment from the BM to the liver is mediated by a liver-specific, KC-derived CC-chemokine gradient of CCL2 and CCL3 that attracts CCR2+ CCR5+ monocytes to the organ.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Theurl I, Hilgendorf I, Nairz M, Tymoszuk P, Haschka D, Asshoff M, He S, Gerhardt LM, Holderried TA, Seifert M, Sopper S, Fenn AM, Anzai A, Rattik S, McAlpine C, Theurl M, Wieghofer P, Iwamoto Y, Weber GF, Harder NK, Chousterman BG, Arvedson TL, McKee M, Wang F, Lutz OM, Rezoagli E, Babitt JL, Berra L, Prinz M, Nahrendorf M, Weiss G, Weissleder R, Lin HY, Swirski FK (2016a) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945–951 source

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  • Premisecitation

    HIF-HRE interaction in response to hypoxia stimulates iron release from macrophages by inducing Hmox1 and Fpn1 as well as ceruloplasmin.

    “HIF-HRE interaction in response to hypoxia thus stimulates iron release from macrophages by inducing Hmox1 and Fpn1 as well as one of its associated ferroxidases, ceruloplasmin [37, 63, 200].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Chiabrando D, Fiorito V, Marro S, Silengo L, Altruda F, Tolosano E (2012) Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice. Blood Cells Mol Dis 50:25–30 source

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    • cites [63] Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL, Johnson RS, Imityaz HZ, Simon MC, Fredlund E, Greten FR, Rius J, Lewis CE (2009) Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114:844–859 source

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    • cites [200] Sarkar J, Seshadri V, Tripoulas NA, Ketterer ME, Fox PL (2003) Role of ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem 278:44018–44024 source

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  • May combine two claims. 45
  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 1

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    Premisecitation

    The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators.

    “The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [171] Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342 source

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    • cites [229] Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G (2009) Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 113:5277–5286 source

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  • May combine two claims.

    Interpretationreasoning

    The molecular machinery of RBC recycling is relatively well described, and its function is essential to tissue integrity given the pro-oxidative capacity of free labile heme.

    “The molecular machinery of RBC recycling is relatively well described, and its function is essential to tissue integrity given the pro-oxidative capacity of free labile heme.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fpn1 is the sole cellular efflux protein for ionic iron, shuttling apically absorbed iron to the circulation, where it is oxidized and loaded onto transferrin.

    “It is at this location that ferroportin-1 (Fpn1; AKA solute carrier family 40 member 1) fulfills its function as the sole cellular efflux protein for ionic iron, shuttling apically absorbed iron to the circulation, where it is oxidized and loaded onto transferrin (TF) [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004b) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093 source

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  • May combine two claims.

    Premisecitation

    SpiC is essential to the development of RPM and EIM, as Spic−/− mice have drastically reduced numbers of RPM and EIM leading to reduced proerythroblast numbers in the steady state, supporting the idea that iron recycling is essential to sustain iron-sufficient erythropoiesis.

    “It is essential to the development of these cell types as Spic −/− mice have drastically reduced numbers of RPM and EIM which lead to reduced proerythroblast numbers in the steady state, supporting the idea that iron recycling is essential to sustain iron-sufficient erythropoiesis [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR (2005) Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 106:1092–1097 source

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    Premisecitation

    Free heme is an endogenous danger signal, as inflammasome activation via NLRP3 is sensitive to surplus intracellular heme while extracellular free heme can activate TLR4.

    “Furthermore, the inflammasome activation via cryopyrin (AKA NLRP3) is sensitive to surplus intracellular heme while extracellular free heme can activate Toll-like receptor 4 (TLR4), supporting the idea that free heme is an endogenous danger signal [60, 65, 66, 131].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [60] Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, Bozza MT (2014) Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci U S A 111:E4110–E4118 source

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    • cites [65] Fernandez PL, Dutra FF, Alves L, Figueiredo RT, Mourao-Sa D, Fortes GB, Bergstrand S, Lonn D, Cevallos RR, Pereira RM, Lopes UG, Travassos LH, Paiva CN, Bozza MT (2010) Heme amplifies the innate immune response to microbial molecules through spleen tyrosine kinase (Syk)-dependent reactive oxygen species generation. J Biol Chem 285:32844–32851 source

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    • cites [66] Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, Oliveira MF, Oliveira PL, Graca-Souza AV, Bozza MT (2007) Characterization of heme as activator of Toll-like receptor 4. J Biol Chem 282:20221–20229 source

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    • cites [131] Li Q, Fu W, Yao J, Ji Z, Wang Y, Zhou Z, Yan J, Li W (2014a) Heme induces IL-1beta secretion through activating NLRP3 in kidney inflammation. Cell Biochem Biophys 69:495–502 source

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  • May combine two claims.

    Interpretationcitation

    Cardiac macrophages may either tailor the delivery of iron to the myocardium or accumulate and detoxify heme which may mainly arise from tissue injury.

    “In addition, their roles in the metabolic activity of the adjacent myocardium and in chronic cardiac diseases such as congestive heart failure are increasingly appreciated [199], and macrophages may either tailor the delivery of iron to the myocardium or accumulate and detoxify heme which may mainly arise from tissue injury [161, 214].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [161] Nahrendorf M, Swirski FK (2016) Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J 37:868–872 source

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    • cites [214] Sohn YS, Ghoti H, Breuer W, Rachmilewitz E, Attar S, Weiss G, Cabantchik ZI (2012) The role of endocytic pathways in cellular uptake of plasma non-transferrin iron. Haematologica 97:670–678 source

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  • May combine two claims.

    Premisecitation

    Iron-mediated generation of ROS and injury to mitochondria are likely mechanisms of NBIA.

    “Although iron-mediated generation of ROS and injury to mitochondria are likely mechanisms [196, 204]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [196] Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14:551–564 source

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    • cites [204] Schipper HM (1999) Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases. Neurotox Res 1:57–70 source

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

    Premisecitation

    Neuroferritinopathy is a rare NBIA condition caused by a mutation in the coding region of the FTL gene.

    “A paradigmatic yet rare NBIA condition is the neuroferritinopathy that is caused by a mutation in the coding region of the FTL gene [44, 45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Cozzi A, Santambrogio P, Privitera D, Broccoli V, Rotundo LI, Garavaglia B, Benz R, Altamura S, Goede JS, Muckenthaler MU, Levi S (2013) Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. J Exp Med 210:1779–1791 source

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    • cites [45] Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Neuronal iron efflux is insufficient to remove surplus and potentially harmful iron from the cytoplasm.

    “It would appear that neuronal iron efflux is insufficient to remove surplus and potentially harmful iron from the cytoplasm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Müller glial cells and endothelial cells of the retina both express Fpn1, but only endothelial cells are sensitive to hepcidin regulation.

    “Müller glial cells and endothelial cells of the retina both express Fpn1, but only the latter cell type is sensitive to hepcidin regulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [232] Theurl M, Song D, Clark E, Sterling J, Grieco S, Altamura S, Galy B, Hentze M, Muckenthaler MU, Dunaief JL (2016b) Mice with hepcidin-resistant ferroportin accumulate iron in the retina. FASEB J 30:813–823 source

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

    Premisecitation

    Arthropathy of the second and third metacarpophalangeal joints is a typical manifestation of type I hemochromatosis.

    “Arthropathy of the second and third metacarpophalangeal joints is a typical manifestation of type I hemochromatosis [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Heiland GR, Aigner E, Dallos T, Sahinbegovic E, Krenn V, Thaler C, Weiss G, Distler JH, Datz C, Schett G, Zwerina J (2010) Synovial immunopathology in haemochromatosis arthropathy. Ann Rheum Dis 69:1214–1219 source

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

    Premisecitation

    Systemic administration of hepcidin-antagonist LDN-193189 blocked the differentiation of macrophages into foam cells and reduced atherosclerotic lesion size.

    “Importantly, LDN treatment also reduced atherosclerotic lesion size, suggesting that modulating systemic iron metabolism affects atherosclerosis progression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, Rostad B, Pachura K, Adams L, Elliott J, Taylor WR, Narula J, Kolodgie F, Virmani R, Hong CC, Finn AV (2012) Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 32:299–307 source

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  • May combine two claims.

    Premisecitation

    Experimental light damage to the retina results in microglial activation, migration to the outer retina, and induction of ferritin H and L chains.

    “In addition, experimental light damage to the retina results in microglial activation, its migration to the outer retina, and in induction of FT H and L chains.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [217] Song D, Song Y, Hadziahmetovic M, Zhong Y, Dunaief JL (2012a) Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic Biol Med 53:64–71 source

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

    Premisecitation

    Lcn2 affects a variety of brain functions from cognition to emotional stress.

    “Notably, Lcn2 also affects a variety of brain functions from cognition to emotional stress [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Jha MK, Lee S, Park DH, Kook H, Park KG, Lee IK, Suk K (2014) Diverse functional roles of lipocalin-2 in the central nervous system. Neurosci Biobehav Rev 49:135–156

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  • May combine two claims.

    Premisenone given

    After experimental intracranial hemorrhage, microglia clear RBC but may also sustain inflammation and cause secondary damage.

    “For instance, after experimental intracranial hemorrhage (ICH), microglia clear RBC but may also sustain inflammation and cause secondary damage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglia are exquisitely sensitive to the potential toxicity of IONs because they are rapidly degraded within lysosomes and their iron catalyzes ROS generation.

    “However, microglia are also exquisitely sensitive to the potential toxicity of IONs because they are rapidly degraded within lysosomes and their iron catalyzes ROS generation [184].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Petters C, Thiel K, Dringen R (2015) Lysosomal iron liberation is responsible for the vulnerability of brain microglial cells to iron oxide nanoparticles: comparison with neurons and astrocytes. Nanotoxicology 10:332–342 source

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  • May combine two claims.

    Premisecitation

    Photoreceptors are sensitive to iron toxicity, and local iron regulatory circuits including the hepcidin-Fpn1 axis operate in the retina.

    “Since photoreceptors are sensitive to iron toxicity, local iron regulatory circuits including the hepcidin-Fpn1 axis operate in the retina [261].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261] Zhao L, Li Y, Song D, Song Y, Theurl M, Wang C, Cwanger A, Su G, Dunaief JL (2014) A high serum iron level causes mouse retinal iron accumulation despite an intact blood-retinal barrier. Am J Pathol 184:2862–2867 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The retina is another organ that is sensitive to iron toxicity but has evidence of endogenous mechanisms to maintain local iron homeostasis in the microenvironment.

    “Therefore, the retina is another organ that is sensitive to iron toxicity but has evidence of endogenous mechanisms to maintain local iron homeostasis in the microenvironment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The composition of ferritin is cell type-specific, and central neuronal ferritin is L chain-rich.

    “The composition of FT is cell type-specific, and central neuronal FT are L chain-rich [236].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [236] Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99:3505–3516 source

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

    Premisecitation

    Hyperferritinemia-cataract syndrome is caused by a mutation in the iron-responsive element of the FTL gene and is not associated with brain iron accumulation but with ferritin crystals in ocular lenses causing early adulthood cataracts.

    “Interestingly, the hyperferritinemia-cataract syndrome that is caused by a mutation in a specific non-coding region of the FTL gene, the iron-responsive element (IRE), is not associated with iron accumulation in the brain but with the formation of ferritin crystals in the ocular lenses, resulting in cataracts in early adulthood [23, 83, 195].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Brooks DG, Manova-Todorova K, Farmer J, Lobmayr L, Wilson RB, Eagle RC Jr, St Pierre TG, Stambolian D (2002) Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome. Invest Ophthalmol Vis Sci 43:1121–1126

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    • cites [83] Girelli D, Corrocher R, Bisceglia L, Olivieri O, De Franceschi L, Zelante L, Gasparini P (1995) Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”). Blood 86:4050–4053 source

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    • cites [195] Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2:406–414 source

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  • May combine two claims.

    Premisecitation

    Osteoclast precursors take up iron via Tfr1 and utilize Steap4 as ferrireductase.

    “Osteoclast precursors take up iron via Tfr1 and utilize six-transmembrane epithelial antigen of prostate (Steap4) as ferrireductase [262].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [262] Zhou J, Ye S, Fujiwara T, Manolagas SC, Zhao H (2013) Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation. J Biol Chem 288:30064–30074 source

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    Premisecitation

    An increase in plasma iron stimulates hepcidin secretion which dampens macrophage iron egress and to a lesser extent duodenal iron absorption following its interaction with Fpn1.

    “An increase in plasma iron stimulates hepcidin secretion which dampens macrophage iron egress and to a lesser extent duodenal iron absorption following its interaction with Fpn1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB (2015) Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 126:1981–1989 source

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    Premisecitation

    Erythroblasts expel their nuclei during differentiation and these are taken up by EIM after phosphatidylserine exposure via Tim4 and MerTK.

    “It is well characterized that erythroblasts expel their nuclei during differentiation and that these are taken up by EIM after phosphatidylserine exposure via Tim4 and MER proto-oncogene, tyrosine kinase (MerTK) [234, 254].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [234] Toda S, Segawa K, Nagata S (2014) MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands. Blood 123:3963–3971 source

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    • cites [254] Yoshida H, Kawane K, Koike M, Mori Y, Uchiyama Y, Nagata S (2005) Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437:754–758 source

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    Premisecitation

    Dmt1 only accepts ferrous iron along with other divalent cations and co-localizes with an iron reductase.

    “At either location, Dmt1 only accepts ferrous iron along with other divalent cations, such as copper or manganese, and co-localizes with an iron reductase [152, 177].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [152] McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755–1759 source

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    • cites [177] Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD (2005) Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37:1264–1269 source

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    Premisecitation

    Siderophores are best characterized in bacteria, but eukaryotes including fungi and mammals produce siderophores too.

    “These are best characterized in bacteria, but eukaryotes including fungi and mammals produce siderophores, too [16, 42, 67, 86, 106].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [16] Behnsen J, Raffatellu M (2016) Siderophores: more than stealing iron. MBio 7:e01397–16 source

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    • cites [42] Correnti C, Strong RK (2012) Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool. J Biol Chem 287:13524–13531 source

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    • cites [67] Fischbach MA, Lin H, Liu DR, Walsh CT (2006) How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2:132–138 source

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    • cites [86] Haas H (2014) Fungal siderophore metabolism with a focus on Aspergillus fumigatus. Nat Prod Rep 31:1266–1276 source

      Not checked in the free run.

    • cites [106] Jones RL, Peterson CM, Grady RW, Cerami A (1980) Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth. J Exp Med 151:418–428 source

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    Premisecitation

    Membrane VCAM1 is expressed on CD169+ macrophages in the spleen and provides a molecular anchor to retain hematopoietic stem cells in the murine spleen.

    “In addition, membrane VCAM1 is expressed on CD169+ macrophages in the spleen and provides a molecular anchor to retain hematopoietic stem cells in the murine spleen, although it is unclear whether this is also relevant to arthropathy [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Dutta P, Hoyer FF, Grigoryeva LS, Sager HB, Leuschner F, Courties G, Borodovsky A, Novobrantseva T, Ruda VM, Fitzgerald K, Iwamoto Y, Wojtkiewicz G, Sun Y, Da Silva N, Libby P, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M (2015) Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. J Exp Med 212:497–512 source

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  • May combine two claims.

    Premisecitation

    Macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload.

    “At the cell surface membrane, macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, Kingsley PD, De Domenico I, Vaughn MB, Kaplan J, Palis J, Abkowitz JL (2008) A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319:825–828 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The functions of IRPs1 and 2 are redundant in macrophages and only targeted deletion of both isoforms via LysM-Cre results in increased FT levels and intracellular iron retention.

    “Interestingly, the functions of IRPs1 and 2 are redundant in macrophages and only targeted deletion of both isoforms via the LysM-Cre system results in increased FT levels and intracellular iron retention [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Recalcati S, Alberghini A, Campanella A, Gianelli U, De Camilli E, Conte D, Cairo G (2006) Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Haematologica 91:303–310

      Not checked in the free run.

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

    Premisecitation

    Circulating VCAM1 is shed by ADAM17 which is activated by inflammatory stimuli.

    “Of interest, circulating VCAM1 is shed by the metalloproteinase ADAM metallopeptidase domain 17 (ADAM17, AKA TNF alpha-converting enzyme (TACE)) which is activated by inflammatory stimuli [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Garton KJ, Gough PJ, Philalay J, Wille PT, Blobel CP, Whitehead RH, Dempsey PJ, Raines EW (2003) Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem 278:37459–37464 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HRG1 shifts heme from the endosome/lysosome to the cytoplasm and Hmox1 metabolizes heme.

    “Its two major functional components are HRG1 which shifts heme from the endosome/lysosome to the cytoplasm and Hmox1 which then metabolizes heme [117].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Korolnek T, Hamza I (2014) Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol 5:126 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of Fpn1 by LysM-Cre results in iron accumulation in macrophages, including bone marrow macrophages, and mild anemia.

    “However, the deletion of Fpn1 by Cre recombinase expressed under the lysozyme M promoter results in iron accumulation in macrophages, including BM macrophages, and mild anemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, Nie G, Knutson MD, Anderson GJ, Wang F (2011) Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118:1912–1922 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LysM-Cre FTH mice have no apparent phenotype suggesting that iron storage and trafficking are well controlled in myeloid cells by other mechanisms.

    “However, LysM-Cre FTH mice have no apparent phenotype suggesting that iron storage and trafficking are well controlled in myeloid cells by other mechanisms [46, 239].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Darshan D, Vanoaica L, Richman L, Beermann F, Kuhn LC (2009) Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage. Hepatology 50:852–860 source

      Not checked in the free run.

    • cites [239] Vanoaica L, Darshan D, Richman L, Schumann K, Kuhn LC (2010) Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab 12:273–282 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    EIM utilize Fpn1 to export iron and thus function as iron-rich nurse cells.

    “This suggests that EIM utilize Fpn1 to export iron and thus function as iron-rich nurse cells [259].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, Nie G, Knutson MD, Anderson GJ, Wang F (2011) Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118:1912–1922 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EIM express the αV integrin which binds ICAM4 on erythroid cells, and ICAM4 KO mice have reduced numbers of erythropoietic islands.

    “For instance, EIM express the αV integrin which binds ICAM4 on erythroid cells, and ICAM4 KO mice have reduced numbers of erythropoietic islands [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Lee G, Lo A, Short SA, Mankelow TJ, Spring F, Parsons SF, Yazdanbakhsh K, Mohandas N, Anstee DJ, Chasis JA (2006) Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation. Blood 108:2064–2071 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tfr1 is widely expressed by isolated macrophages and may form a major route of iron uptake in the absence of RBC, though it also appears important in adaptive immunity.

    “Tfr1, which is also known as CD71, is widely expressed by isolated macrophages, and it may form a major route of iron uptake in the absence of RBC (an indirect iron source), though it also appears to be important in adaptive immunity [103, 138].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet 48:74–78 source

      Not checked in the free run.

    • cites [138] Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101:4148–4154 source

      Not checked in the free run.

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

    Premisecitation

    Some mammalian siderophores such as catechols are probably synthesized from commensal metabolites or dietary precursors.

    “While some of these compounds such as citrate are ubiquitous substrates, other mammalian siderophores such as catechols are probably synthesized from commensal metabolites or dietary precursors [11, 50, 252].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T, Kulkarni R, Li X, Lee B, Kalandadze A, Ratner AJ, Pizarro JC, Schmidt-Ott KM, Landry DW, Raymond KN, Strong RK, Barasch J (2010) Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol 6:602–609 source

      Not checked in the free run.

    • cites [50] Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006–1017 source

      Not checked in the free run.

    • cites [252] Xiao X, Yeoh BS, Saha P, Tian Y, Singh V, Patterson AD, Vijay-Kumar M (2016) Modulation of urinary siderophores by the diet, gut microbiota and inflammation in mice. J Nutr Biochem 41:25–33 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SpiC and its down-stream effector Hmox1 are both essential for EIM differentiation, since ablation of either gene reduces EIM number.

    “The transcription factor SpiC and its down-stream effector Hmox1 are both essential for EIM differentiation, since ablation of either gene reduces EIM number [73, 88].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Fraser ST, Midwinter RG, Coupland LA, Kong S, Berger BS, Yeo JH, Andrade OC, Cromer D, Suarna C, Lam M, Maghzal GJ, Chong BH, Parish CR, Stocker R (2015) Heme oxygenase-1 deficiency alters erythroblastic island formation, steady-state erythropoiesis and red blood cell lifespan in mice. Haematologica 100:601–610 source

      Not checked in the free run.

    • cites [88] Haldar M, Kohyama M, So AY, Kc W, Wu X, Briseno CG, Satpathy AT, Kretzer NM, Arase H, Rajasekaran NS, Wang L, Egawa T, Igarashi K, Baltimore D, Murphy TL, Murphy KM (2014) Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 156:1223–1234 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dmt1 shifts iron from the extracellular space to the cytoplasm and, in its alternately spliced form, from the Tfr1 endosome to the cytoplasm.

    “Dmt1 shifts iron from the extracellular space to the cytoplasm and, in its alternately spliced form, from the Tfr1 endosome to the cytoplasm [69, 99, 139].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U S A 95:1148–1153 source

      Not checked in the free run.

    • cites [99] Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A 99:12345–12350 source

      Not checked in the free run.

    • cites [139] Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G (2007) Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med 13:448–454 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salmonella Typhimurium preferentially infects murine macrophages and has a proliferative advantage in the absence of both IRPs resulting in increased bacterial burden and reduced survival in a systemic infection model.

    “This pathogen preferentially infects murine macrophages and has a proliferative advantage in the absence of both IRPs resulting in increased bacterial burden and reduced survival in a systemic infection model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Nairz M, Ferring-Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015a) Iron regulatory proteins mediate host resistance to salmonella infection. Cell Host Microbe 18:254–261 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of both IRPs in macrophages does not affect RBC recycling but impairs their nutritional immune functions against intracellular bacteria such as Salmonella Typhimurium.

    “The deletion of both IRPs in macrophages does not affect RBC recycling but impairs their nutritional immune functions against intracellular bacteria, such as Salmonella Typhimurium [166].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Nairz M, Ferring-Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015a) Iron regulatory proteins mediate host resistance to salmonella infection. Cell Host Microbe 18:254–261 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages express a range of factors mediating iron uptake and essentially face only two pathways for iron efflux, Fpn1 for ionic iron and Flvcr for heme iron, although alternative routes may exist.

    “Macrophages express a range of factors mediating iron uptake (summarized in the Table 1) which essentially face only two pathways for iron efflux, Fpn1 for ionic iron and feline leukemia virus subtype C receptor (Flvcr) for heme iron (Fig. 2), although alternatives routes may exist [49, 136].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Devireddy LR, Gazin C, Zhu X, Green MR (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–1305 source

      Not checked in the free run.

    • cites [136] Lok HC, Sahni S, Jansson PJ, Kovacevic Z, Hawkins CL, Richardson DR (2016) A nitric oxide storage and transport system that protects activated macrophages from endogenous nitric oxide cytotoxicity. J Biol Chem 291:27042–27061 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron alters gene transcription, translation, and mitochondrial respiration in macrophages.

    “Second, iron alters gene transcription, translation, and mitochondrial respiration in macrophages [165, 175].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [165] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5:152 source

      Not checked in the free run.

    • cites [175] Oexle H, Gnaiger E, Weiss G (1999) Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta 1413:99–107 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Iron stimulates the non-enzymatic generation of ROS which may promote antimicrobial activity but contribute to tissue damage and pathogenesis of inflammatory disorders.

    “In contrast to its inhibitory effect on NO, iron stimulates the non-enzymatic generation of ROS which may promote their antimicrobial activity but contribute to tissue damage and the pathogenesis of many inflammatory disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    This pathway is important for iron recycling after erythrophagocytosis and serves as a mechanism of nutrient withdrawal efficient in host defense against Mycobacterium, Salmonella, and Leishmania species.

    “This pathway is important for iron recycling after erythrophagocytosis [213] and serves as a mechanism of nutrient withdrawal that is particularly efficient in host defense against Mycobacterium, Salmonella, and Leishmania species [31].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [213] Soe-Lin S, Apte SS, Andriopoulos B Jr, Andrews MC, Schranzhofer M, Kahawita T, Garcia-Santos D, Ponka P (2009) Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci U S A 106:5960–5965 source

      Not checked in the free run.

    • cites [31] Cellier MF (2012) Nramp: from sequence to structure and mechanism of divalent metal import. Curr Top Membr 69:249–293 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These effects may contribute to inflammatory characteristics of sickle cell disease and can be ameliorated by the heme scavenger HPX.

    “These effects may contribute to the inflammatory characteristics of sickle cell disease and can be ameliorated by the heme scavenger HPX.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The functional form of Nramp1 in myeloid cells shifts the balance in T helper cell activity towards Th1, which may increase resistance to infections while increasing susceptibility to autoimmune diseases.

    “In addition, the functional form of Nramp1 in myeloid cells shifts the balance in T helper cell activity towards Th1, which may increase resistance to infections while increasing the susceptibility to autoimmune diseases [167, 226].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G (2015b) 'Ride on the ferrous wheel'—the cycle of iron in macrophages in health and disease. Immunobiology 220:280–294 source

      Not checked in the free run.

    • cites [226] Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G (2005) The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals 18:359–367 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR4 signaling stabilizes HIF-1α activation via induction of FTH and hypoxia stimulates arginase-1 expression in myeloid cells thus undermining Leishmania killing.

    “Another layer of complexity is added by the fact that TLR4 signaling stabilizes HIF-1α activation via induction of FTH and hypoxia stimulates arginase-1 expression in myeloid cells thus undermining Leishmania killing [142, 209].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [142] Mahnke A, Meier RJ, Schatz V, Hofmann J, Castiglione K, Schleicher U, Wolfbeis OS, Bogdan C, Jantsch J (2014) Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages. J Invest Dermatol 134:2339–2346 source

      Not checked in the free run.

    • cites [209] Siegert I, Schodel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, Schley G, Beneke A, Sutter J, Moll M, Hellerbrand C, Wielockx B, Katschinski DM, Lang R, Galy B, Hentze MW, Koivunen P, Oefner PJ, Bogdan C, Weiss G, Willam C, Jantsch J (2015) Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1alpha upon LPS activation in the presence of ample oxygen. Cell Rep 13:2048–2055 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The other study suggested that IONs stimulate TNF expression while inhibiting arginase-1 which results in improved killing of tumor cells.

    “The other study suggested that IONs stimulate TNF expression while inhibiting arginase-1 which results in improved killing of tumor cells [257].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [257] Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik H, Goodman S, Moseley M, Coussens LM, Daldrup-Link HE (2016) Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol 11:986–994 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The two modes of HIF activation are distinct: TLR4 signaling depletes iron as co-substrate for PHDs, while hypoxia impairs PHD activity due to lack of oxygen.

    “Mechanistically, these two modes of HIF activation are distinct. While TLR4 signaling results in depletion of iron as co-substrate which prolyl hydroxylases (PHDs) require to tag HIF for degradation, hypoxia, per definition, impairs PHD activity due to a lack of their substrate oxygen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Under physiologic conditions, macrophages recycle the iron for erythropoiesis, while under hemolytic stress, macrophages detoxify heme to prevent iron toxicity towards parenchymal cells and tissues.

    “Under physiologic conditions, macrophages recycle the iron for erythropoiesis, while under hemolytic stress, macrophages detoxify heme to prevent iron toxicity towards parenchymal cells and tissues.”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    No regulated pathway of iron excretion exists in the mammalian organism.

    “It is generally thought that no regulated pathway of iron excretion exists in the mammalian organism.”
1 of 1

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?

  • Free heme and hemoglobin released during red blood cell lysis are bound by hemopexin and haptoglobin, respectively, and taken up by cells expressing CD91 and CD163.

    “Furthermore, free heme and hemoglobin released during red blood cell (RBC) lysis are bound in the circulation by hemopexin and haptoglobin, respectively, and these iron-containing complexes are then taken up by cells expressing the CD91 and CD163 receptors (Nairz et al., 2017).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2017

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Hemopexin and haptoglobin are assigned opposite binding partners

    Minor

    The first passage says hemopexin binds hemoglobin and haptoglobin binds heme. A later passage reverses those assignments.

1 of 1

Cites

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2 of the 269 references couldn’t be matched to a known paper.

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Related

Authors
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G.
Affiliations
  • Harvard University (US)
  • Innsbruck Medical University (AT)
Corresponding author
Nairz, Manfred
ORCID
Venue
Pflügers Archiv - European Journal of Physiology
Publisher
Springer Science and Business Media LLC
Published
2017-03-01
Volume
469
Issue
3-4
Pages
397-418
ISSN
  • 0031-6768 (ISSN-L)
  • 1432-2013
DOI
10.1007/s00424-017-1944-8
PMC
PMC5362662
OpenAlex
W2592213450
Semantic Scholar
223e4460dd3f67b8a384962555fdeab9e69defd4
Cited by
178
References
269
Citations by year
2026: 8 · 2025: 15 · 2024: 15 · 2023: 22 · 2022: 23 · 2021: 28 · 2020: 31 · 2019: 14 · 2018: 17 · 2017: 4
FWCI
2.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Pflügers Archiv - European Journal of Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
University of Innsbruck and Medical University of Innsbruck
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Physical Sciences › Engineering › Mechanical Engineering › Iron and Steelmaking Processes
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
macrophages, iron homeostasis, iron metabolism, heme detoxification, hemoglobin synthesis, spleen, liver, bone marrow, tissue microenvironment, innate immunity, erythropoiesis
MeSH terms
Animals, Erythropoiesis, Homeostasis, Humans, Iron, Macrophages, Cellular Microenvironment

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.

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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