CoChat
Sign Up
Cited by 299Iron Metabolism and DisordersFerroptosis and cancer prognosisImmune cells in cancer

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Open access
Cronin, Shane J. F., Woolf, Clifford J., Weiss, Guenter, Penninger, Josef M.·2019·Frontiers in Molecular Biosciences
DOI 10.3389/fmolb.2019.00116PMC PMC6883604
Open this paper in CoChat — free accountOpen PDF

Abstract

Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes how iron uptake, storage, export, and mitochondrial utilization regulate immune cell metabolism and function, with emphasis on nutritional immunity, macrophage polarization, T cell activation, and BH4-dependent iron reduction. It argues that targeting iron/BH4 pathways offers therapeutic opportunities in autoimmunity and cancer.

Key findings

  • The iron cycle is tightly controlled: humans absorb 1–2 mg of iron daily, macrophages recycle ~90–95% of daily iron needs, and hepcidin degrades ferroportin to retain iron intracellularly. Hepatic iron deposits normally range from 300 mg to 1 g but can reach 25–30 g in hereditary hemochromatosis.
  • Nutritional immunity shapes infection outcomes: iron overload increases susceptibility to pathogens such as *Vibrio vulnificus*, while mild iron deficiency is protective against *Plasmodium falciparum* malaria; pathogens can hijack transferrin/ferroportin, and lipocalin-2 counters siderophore-mediated bacterial iron acquisition.
  • Immune cell subsets use iron differently: neutrophils rely on myeloperoxidase (~5% of total neutrophil protein) and iron-scavenging lactoferrin/calprotectin; M1 macrophages are iron-retaining whereas M2 macrophages are iron-releasing; T cells upregulate transferrin receptor (TFR/CD71) within a minute of TCR engagement, and TFRC mutation causes combined immunodeficiency.
  • BH4 links iron to T cell metabolism: GCH1 is induced after TCR stimulation, BH4 reduces cytochrome C-Fe3+ to cytochrome C-Fe2+, and BH4 deficiency impairs mitochondrial respiration, increases ROS, and alters mitoferrin, HO-1, ferritin, and frataxin; the SPR inhibitor QM385 blocks T cell proliferation at nanomolar potency and reduces autoimmunity in several models.

Methods

  • Narrative review; no primary experiments or systematic analysis.
  • Synthesizes literature on cellular and systemic iron metabolism, immunometabolism, immune-related disease, and the authors’ prior work on BH4 in T cells.
  • Main analysis is conceptual, with Figure 1, Figure 2, Figure 4, and Table 1 summarizing iron cycle components and regulatory mechanisms.

Limitations

  • Not stated in the paper: the review does not include an explicit limitations section.
  • Evident: as a narrative review, it lacks a systematic search strategy, meta-analysis, or primary data to assess bias or effect sizes.
  • Evident: conclusions rely on cited studies and the authors’ own prior BH4 work, and the broad scope means some areas are covered selectively rather than exhaustively.

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

Integrity signals

Registry

Crossref · 10.3389/fmolb.2019.00116

Cites

208 of 208 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 238 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Enhancing BH4 production, either genetically or pharmacologically, results in hyper-activated T cells displaying stronger effector functions.

    “Furthermore, by enhancing BH4 production, either genetically or pharmacologically, we observed an opposing phenotype, where the T cells are hyper-activated, displaying stronger effector functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • Findingcitation

    BH4 alone, in a co-factor independent manner, can reduce cytochrome-C-Fe3+ to cytochrome-C-Fe2+ at physiological concentrations and efficacy.

    “Moreover, we confirmed data from almost 50 years ago that BH4 alone, in a co-factor independent manner, can reduce cytochrome-C-Fe3+ to cytochrome-C-Fe2+ at physiological concentrations and efficacy (Archer et al., 1972; Figure 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Archer et al., 1972 source

      Not checked in the free run.

  • Findingcitation

    The mitochondrial respiration defect in Gch1-ablated T cells after stimulation can be rescued by supplying reduced cytochrome-C-Fe2+ directly to the mitochondria.

    “We could rescue the mitochondrial respiration defect by supplying reduced cytochrome-C-Fe2+ directly to the mitochondria of Gch1-ablated T cells after stimulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • Findingown data

    BH4-deficient T cells after activation show overall depletion of total iron.

    “We observed an overall depletion of total iron in T cells after activation under BH4-deficient conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • Findingcitation

    GCH1 is expressed in T cells but only after TCR stimulation.

    “We and others have shown that GCH1 is expressed in T cells but only after TCR stimulation (Chen et al., 2011; Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Chen et al., 2011 source

      Not checked in the free run.

    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims. 75
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingreasoning

    Under BH4 deficiency, T cells show dysfunctional ETC, enhanced ROS, and reduced ATP production in activated T cells.

    “Under BH4 deficiency, T cells show dysfunctional ETC, enhanced ROS, and reduced ATP production in activated T cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Under BH4 deficiency, cytochrome-C reduction is compromised, resulting in dysfunctional mitochondrial respiration, increased superoxide formation, and diminished ATP production.

    “Under conditions of BH4 deficiency, as in our Gch1-ablated T cells, cytochrome-C reduction is compromised, resulting in dysfunctional mitochondrial respiration, increased superoxide formation and, ultimately diminished ATP production, all of which we observed (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Genetic inactivation of GCH1 or pharmacological inhibition of SPR results in severely impaired proliferation of T cells.

    “Using multiple T cell specific ablation strategies, we demonstrated that genetic inactivation of GCH1 or pharmacological inhibition of the terminal enzyme in the biosynthetic pathway of BH4, sepiapterin reductase (SPR), results in severely impaired proliferation of T cells (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    T cell development or homeostasis as well as B cell and regulatory T cell functions are unaffected by inhibition of the BH4 pathway.

    “However, interestingly, T cell development or homeostasis as well as B cell and regulatory T cell (Treg) functions are unaffected by inhibition of this pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    Under BH4 deficiency, T cells show dysregulated Mitoferrin, Frataxin, HO-1, Ferritin and overall reduced iron levels in the cell.

    “Moreover, the T cells show dysregulated Mitoferrin, Frataxin, HO-1, Ferritin and overall reduced iron levels in the cell”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    BH4 can act as a superoxide ROS scavenger and directly reduce Fe3+ to Fe2+, thereby affecting cytochrome C activity in the ETC.

    “BH4 can not only act as a superoxide ROS scavenger but also directly reduce Fe3+ to Fe2+ and therefore affect cytochrome C (cyto-C) activity in the ETC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In genetic inactivation models, there were no differences in iNOS expression or NO production in T cells, nor detectable signs of activated T cells producing biogenic amine neurotransmitters that require co-factor BH4.

    “In genetic inactivation models, we did not detect any differences in iNOS expression or NO production in T cells, nor any detectable signs of activated T cells producing biogenic amine neurotransmitters that require co-factor BH4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In orthotopic cancer transfer models, BH4-overproducing T cells have increased anti-cancer immunity, resulting in greatly reduced cancer burden.

    “In orthotopic cancer transfer models, BH4-overproducing T cells have increased anti-cancer immunity, resulting in greatly reduced cancer burden (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    QM385 is a novel BH4 inhibitor that targets SPR.

    “To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In activated T cells, BH4 regulates both the reduction of Fe3+ and increases the availability of Fe2+ in the cell, which aid activated T cells in coordinating the increased metabolic needs for effector functions.

    “In such activated T cells, BH4 regulates both the reduction of Fe3+ and increases the availability of Fe2+ in the cell, which aid activated T cells in coordinating the increased metabolic needs for effector functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

    • Rests on an assumption: Fe2+ is needed for metalloproteins like cytochrome-C to function optimally, for Fe-S cluster biogenesis, which are essential for complex I and II activity of the ETC, and for heme production.

  • May combine two claims.

    Findingcitation

    QM385 has good oral bioavailability and no observable side-effects at immune suppressant exposures.

    “To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Enhancing BH4 genetically or pharmacologically with BH4 itself causes T cells to display heightened proliferation and increased anti-tumor activity.

    “We also showed that by enhancing BH4 genetically, or pharmacologically with BH4 itself, T cells displayed heightened proliferation and, importantly, increased anti-tumor activity (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    QM385 blocks both mouse and human T cell proliferation at nanomolar potency.

    “To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transferrin is a glycoprotein containing two high affinity binding sites for ferric iron, which captures Fe3+ in the circulation.

    “Transferrin (Tf) is a glycoprotein containing two high affinity binding sites for ferric iron (Fe3+) (Aisen et al., 1978), which captures Fe3+ in the circulation (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aisen et al., 1978 source

      Not checked in the free run.

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

    Premisecitation

    Iron deficiency is the most common pathology of iron homeostasis, eventually resulting in iron deficiency anemia, the most frequent anemia worldwide.

    “Iron deficiency is the most common pathology of iron homeostasis, eventually resulting in iron deficiency anemia, the most frequent anemia worldwide (Camaschella, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Camaschella, 2015 source

      Not checked in the free run.

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

    Premisecitation

    Ferric iron in the circulation is bound by transferrin and carried to cells and tissues.

    “Ferric iron in the circulation is then bound by transferrin (Tf) and carried to cells and tissues (Muckenthaler et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Muckenthaler et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diferric transferrin prevents non-transferrin bound iron from engaging in Fenton chemistry and deprives invading pathogens of free iron.

    “This diferric Tf conjugate (Tf-Fe3+) not only prevents free, non-transferrin bound iron (NTBI), from engaging in Fenton chemistry to produce dangerous hydroxyl radicals, but also deprives invading pathogens of free iron to block their expansion and proliferation (Barber and Elde, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Barber and Elde, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “Accordingly, iron trafficking is controlled by cytokines and acute phase proteins, whereas the metal itself promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism, as we will discuss later (Ganz and Nemeth, 2015; Soares and Weiss, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ganz and Nemeth, 2015 source

      Not checked in the free run.

    • cites Soares and Weiss, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The freed ferric iron is reduced to Fe2+ by STEAP3 and shuttled into the cytosol from the endosome by DMT1.

    “The freed ferric iron is then reduced to its bio-active ferrous form, Fe2+ by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) and shuttled into the cytosol from the endosome by DMT1 (Fleming et al., 1997; Gunshin et al., 1997; Ohgami et al., 2005; Figure 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Fleming et al., 1997 source

      Not checked in the free run.

    • cites Gunshin et al., 1997 source

      Not checked in the free run.

    • cites Ohgami et al., 2005 source

      Not checked in the free run.

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

    Premisecitation

    Heme-conjugated iron is absorbed by enterocytes in the duodenum, although this heme importer has not yet been characterized.

    “It has also been demonstrated that heme-conjugated iron is absorbed by enterocytes in the duodenum although this heme importer has not yet been characterized (Gräsbeck et al., 1979).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gräsbeck et al., 1979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The release of iron from enterocytes is controlled by ferroportin followed by extracellular oxidation to ferric iron by hephaestin.

    “This latter step is controlled by the iron exporter, ferroportin (FPN, also called SLC40A1) followed by extracellular oxidation to ferric iron by the copper enzyme hephaestin (HEPH) (Vulpe et al., 1999; Muckenthaler et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Vulpe et al., 1999 source

      Not checked in the free run.

    • cites Muckenthaler et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When systemic iron levels in the blood stream are low, expression of DMT1 and DcytB ferrireductase increases on the surface of intestinal enterocytes on the luminal side, enabling reduction of Fe3+ to Fe2+ which can then be taken up by DMT1.

    “When systemic iron levels in the blood stream are low, expression of DMT1 (divalent metal transporter 1, also called NRAMP2 as well as SLC11A2) and DcytB (duodenal membrane associated cytochrome-b) ferrireductase increases on the surface of intestinal enterocytes on the luminal side enabling the reduction of Fe3+ into its ferrous form (Fe2+) which can then be taken up by DMT1 (McKie et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McKie et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tf-Fe3+ binds to TFR1 on the surface of cells, and this complex is subsequently endocytosed.

    “Tf-Fe3+ binds to the high-affinity transferrin receptor (TFR1, CD71) on the surface of cells, and this complex is subsequently endocytosed (Harding et al., 1983).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Harding et al., 1983 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepcidin overexpression leads to low plasma iron levels (hypoferremia) and anemia.

    “Hepcidin overexpression leads to low plasma iron levels (hypoferremia) and anemia (Weinstein et al., 2002; Roy et al., 2007; Theurl et al., 2009; Altamura et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Weinstein et al., 2002 source

      Not checked in the free run.

    • cites Roy et al., 2007 source

      Not checked in the free run.

    • cites Theurl et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caenorhabditis elegans fed on a mutant strain of Escherichia coli with reduced iron uptake had diminished iron uptake, impaired mitochondrial ETC function, enhanced ROS production, and developmental defects.

    “Caenorhabditis elegans fed on a mutant strain of Escherichia coli, which exhibits reduced iron uptake, lead to diminished iron uptake by the worms resulting in significantly impaired mitochondrial ETC function, enhanced ROS production and developmental defects (Zhang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepcidin binds to the extracellular part of FPN, targeting it for degradation, preventing iron export and sequestering iron in the cell.

    “Hepcidin then enters the circulation and binds to the extracellular part of FPN targeting it for degradation, thus preventing iron from being exported into the circulation and instead being sequestered in the cell (Nemeth et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nemeth et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Certain cell types rely more heavily on TFR1-mediated iron uptake while other cell types have adapted other mechanisms to import iron.

    “These reports demonstrate how certain cell types rely more heavily on TFR1-mediated iron uptake while other cell types have adapted other mechanisms to import iron into their cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NCOA4-null mice are unable to undergo ferritinophagy, and this increased retention of iron within ferritin complexes results in reduced iron export and iron-deficient anemia.

    “NCOA4 is a key regulator of ferritinophagy and intracellular iron levels—NCOA4-null mice are unable to undergo ferritinophagy and this increased retention of iron within ferritin complexes results in reduced iron export from cells and ultimately in iron-deficient anemia (Bellelli et al., 2014, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bellelli et al., 2014, 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Frataxin has been identified as an important iron regulator of Fe-S biogenesis.

    “The Fe source of the cluster is not yet known, although frataxin (FXN) has been identified as an important iron regulator of Fe-S biogenesis (Colin et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Colin et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nairz et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The key iron exporter is ferroportin, which exports Fe2+ iron.

    “The key iron exporter is ferroportin (FPN, also called SLC40A1) which exports Fe2+ iron (McKie et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McKie et al., 2000 source

      Not checked in the free run.

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

    Premisecitation

    Frataxin has been proposed to provide the iron while GLRX5 acts as a scaffolding protein and may facilitate transfer of Fe-S clusters to target proteins.

    “Frataxin has been proposed to provide the iron while GLRX5 acts not only as a scaffolding protein but may also facilitate the transfer of Fe-S clusters to target proteins (Yoon and Cowan, 2003; Ye et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yoon and Cowan, 2003

      Not checked in the free run.

    • cites Ye et al., 2010

      Not checked in the free run.

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

    Premisecitation

    Hepatic iron deposits can range from 300 mg to 1 g, but can reach 25-30 g in patients with hereditary hemochromatosis.

    “Hepatic iron deposits can range from 300 mg to 1 g, but can reach up to 25–30 g in patients suffering from genetic iron overload, a condition called hereditary hemochromatosis (HH) (Janssen and Swinkels, 2009; Anderson and Shah, 2013; Procaccini and Kowdley, 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Janssen and Swinkels, 2009

      Not checked in the free run.

    • cites Anderson and Shah, 2013

      Not checked in the free run.

    • cites Procaccini and Kowdley, 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NF-kB and NRF2 both increase ferritin transcription.

    “NF-kB, an important integrator transcription factor downstream from multiple inflammatory signals, as well as NRF2 (nuclear factor erythroid 2-related factor-2), the main stress-responsive transcription factor, both increase ferritin transcription (Miller et al., 1991; Pham et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Miller et al., 1991 source

      Not checked in the free run.

    • cites Pham et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron not readily used for metabolic purposes is stored by ferritin, and ferritin-conjugated iron released from various cells is taken up by Scara5 or TIM-2 receptors.

    “Notably, as we discuss later, iron not readily used for metabolic purposes is stored by the protein ferritin and ferritin-conjugated iron released from various cells is taken up by Scara5 (Scavenger receptor class A member 5) or TIM-2 (T Cell Immunoglobulin And Mucin Domain Containing 2) receptors (Chen et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A mitochondrial form of ferritin exists which may protect mitochondria against iron-mediated toxicity and provide a quick source of iron.

    “There also exists a mitochondrial form of ferritin (Levi et al., 2001) which may both protect mitochondria against iron-mediated toxicity and provide a quick and efficient source of iron in this organelle rather than relying solely on the cytosolic ferritin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Levi et al., 2001 source

      Not checked in the free run.

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

    Premisecitation

    Fe-S clusters are ubiquitous inorganic co-factors that contribute to genome integrity, gene regulation, energy production, and immune responses, and are required for numerous biological functions, particularly enzymatic activity.

    “Fe-S clusters are ubiquitous, inorganic co-factors that contribute to a wide range of cellular pathways from genome integrity and gene regulation to energy production and immune responses, and are required for numerous biological functions, particularly enzymatic activity (Beinert, 2000; Johnson et al., 2005; Lee et al., 2009; Fuss et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Beinert, 2000 source

      Not checked in the free run.

    • cites Johnson et al., 2005 source

      Not checked in the free run.

    • cites Lee et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial iron is required for the synthesis of Fe-S clusters, and their biogenesis is thought to be one of the most important functions of mitochondria.

    “Mitochondrial iron is also required for the synthesis of Fe-S clusters and indeed their biogenesis is thought to be one of the most important functions of the mitochondria—even though some Fe-S assembly can occur in the cytosol and nucleus (Tong, 2000; Tong et al., 2003; Tong and Rouault, 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Tong, 2000 source

      Not checked in the free run.

    • cites Tong et al., 2003 source

      Not checked in the free run.

    • cites Tong and Rouault, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gene-ablation murine models and patients deficient in CP and HEPH present with iron-deficient anemia, demonstrating the importance of these oxidases for iron export.

    “The importance of these oxidases for successful iron export into the circulation has been demonstrated with gene-ablation murine models as well as identification of patients deficient in CP and HEPH, presenting with iron-deficient anemia (Yoshida et al., 1995; Hahn et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yoshida et al., 1995 source

      Not checked in the free run.

    • cites Hahn et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salmonella typhimurium secretes a heavily glycosylated siderophore, salmochelin, which is not recognized by lipocalin-2, making these bacteria unresponsive to this host defense strategy.

    “However, pathogens are constantly evolving and adapting to host responses and have created modified siderophores, such as the heavily glycoslyated siderophore, salmochelin, secreted by Salmonella typhimurium, which is not recognized and targeted by lipocalin-2 thus making these bacteria unresponsive to this host defense strategy (Hantke et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hantke et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IRP1 binding to the 3' UTR increases stability of TFR and DMT1 mRNAs, promoting their expression and enhancing iron uptake into the cell.

    “However, IRP1 binding to the 3′ UTR increases the stability of the respective target mRNAs such as TFR and DMT1, thereby promoting their expression and subsequently enhancing iron uptake into the cell to replenish intracellular iron levels.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Salivary peroxidase and lactoperoxidase (LPO) are present in multiple human exocrine secretions, including tears, milk, saliva, and vaginal fluid, and serve anti-microbial killing actions similar to MPO.

    “Other related hemoproteins include salivary peroxidase and lactoperoxidase (LPO) which are present in multiple human exocrine secretions, including tears, milk, saliva, and vaginal fluid, and also serves anti-microbial killing actions similar to MPO (Sarr et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sarr et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erythroferrone is produced by EPO-stimulation of erythroid progenitors and blocks hepcidin synthesis in hepatocytes.

    “Erythroferrone (ERFE) is produced by erythropoietin (EPO)-stimulation of erythroid progenitors and blocks hepcidin synthesis in the hepatocytes (Kautz et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kautz et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils produce large amounts of calprotectin and lactoferrin, both of which scavenge iron, thereby inhibiting bacterial proliferation.

    “In addition, neutrophils produce large amounts of calprotectin and lactoferrin, both of which scavenge iron, thereby inhibiting bacterial proliferation (Nakashige et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nakashige et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with insufficient hepcidin production suffer from iron-overload in the blood and hepatitis.

    “Conversely, individuals with insufficient hepcidin production, suffer from iron-overload in the blood, and hepatitis (Pietrangelo, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pietrangelo, 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IRP2 deficiency switches cellular metabolic pathways from oxidative phosphorylation to aerobic glycolysis through induction of HIF-1α and -2α, which enhances glycolytic pathway proteins and blocks mitochondrial Fe-S cluster biogenesis and OXPHOS.

    “Indeed, IRP2 deficiency switches cellular metabolic pathways from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (Li et al., 2019) through induction of hypoxia-inducible factors (HIF)-1α and−2α which enhances glycolytic pathway proteins and, at the same time, blocks mitochondrial Fe-S cluster biogenesis and OXPHOS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When iron concentrations are low, IRP1 loses its Fe-S cluster, loses catalytic abilities, and binds to IREs in the 5' UTR of ferritin-H and -L and ALAS, inhibiting translation and reducing storage and utilization of iron.

    “When iron concentrations are low, IRP1 loses it Fe-S cluster and, therefore, its catalytic abilities but instead can now bind to IREs in the 5′ UTR of mRNAs such as ferritin-H and -L subunits as well as the rate-limiting enzyme of heme biogenesis, ALAS (aminolevulinic acid synthase) which results in inhibition of their translation and thus reduced storage and utilization of the metal (Figure 2).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Siderophores are low molecular weight iron-binding complexes secreted by bacteria to compete with transferrin for iron sequestration.

    “Siderophores are low molecular weight iron-binding complexes that are secreted by bacteria to compete with transferrin for iron sequestration (Williams, 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Williams, 1988 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Superoxide radicals can free up Fe2+ iron and this can further react with hydrogen peroxide (H2O2) to give rise to hydroxyl radicals (OH•).

    “Superoxide radicals can free up Fe2+ iron and this can further react with hydrogen peroxide (H2O2) to give rise to the hydroxyl radicals (OH•) (Koskenkorva-Frank et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Koskenkorva-Frank et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The availability and restriction of systemic iron during infection and inflammation represents an essential defense mechanism against pathogens but under pathophysiological conditions can lead to anemia and further severe pathologies resulting from reduced RBC development.

    “Therefore, the availability and restriction of systemic iron during times of infection and inflammation represents an essential defense mechanism against pathogens but under pathophysiological conditions can lead to anemia and further severe pathologies resulting from reduced RBC development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When iron levels are low, FBXL5 is degraded due to its Fe-binding N-terminal hemerythrin-like iron-sensing domain undergoing a conformational change, leading to FBXL5 polyubiquitination and degradation, resulting in IRP2 accumulation.

    “However, when iron levels are low, FBXL5 is itself degraded. This is due to a Fe-binding N-terminal hemerythrin-like (Hr) iron-sensing domain in FBXL5. The Hr domain undergoes a conformational change when iron is not present—this structural change leads to FBXL5 polyubiquitination and degradation resulting in IRP2 accumulation (Thompson et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thompson et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Imbalanced iron levels in the cell can lead to dysfunctional mitochondria, increased oxidative damage, and increased toxicity.

    “Imbalanced iron levels in the cell can lead to dysfunctional mitochondria, increased oxidative damage and increased toxicity (Richardson et al., 2010; Volani et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Richardson et al., 2010 source

      Not checked in the free run.

    • cites Volani et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When iron levels normalize, IRP1 regains its Fe-S cluster and aconitase activity, resulting in increased ferritin translation and decreased TFR expression, reducing Fe uptake.

    “When iron levels normalize again, IRP1 regains its Fe-S cluster and aconitase activity. This results in increased ferritin translation and decreased TFR expression, resulting in reduced Fe uptake (Li et al., 2004; Rouault, 2006; Leipuviene and Theil, 2007; Sanchez et al., 2011; Figure 2).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Li et al., 2004

      Not checked in the free run.

    • cites Rouault, 2006 source

      Not checked in the free run.

    • cites Leipuviene and Theil, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages and Kupffer cells scavenge heme from damaged or aged RBCs in the bone marrow, liver and spleen, extract the Fe2+ iron using HO-1, and then either export it back into the circulation through FPN or store it in ferritin intracellularly.

    “Macrophages and Kupffer cells scavenge heme from damaged or aged RBCs in the bone marrow, liver and spleen, and extract the Fe2+ iron using HO-1 and then either exports it back into the circulation through FPN or stores it in ferritin intracellularly (Knutson et al., 2005; Theurl et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Knutson et al., 2005 source

      Not checked in the free run.

    • cites Theurl et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hematopoietic-specific deletion of the ferritin heavy chain (Fth) gene results in reduced numbers of lymphocytes while other cell types such as granulocytes and monocytes are unaffected.

    “Furthermore, hematopoietic-specific deletion of the ferritin heavy chain (Fth) gene results in reduced numbers of lymphocytes while other cell types such as granulocytes and monocytes are unaffected, again highlighting the essential nature of iron regulation to the adaptive immune system (Vanoaica et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vanoaica et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, this reprogramming is done by increased production of nitric oxide (NO), which activates NRF2 resulting in transcriptional induction of FPN expression leading to increased iron export from the cell, thus restricting iron availability to the intracellular pathogen.

    “In mice, this is done by increased production of nitric oxide (NO) (Nairz et al., 2013), which activates the stress-responsive transcription factor, NRF2 resulting in transcriptional induction of FPN expression leading to subsequent increase of iron export from the cell, thus again restricting iron availability to the intracellular pathogen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nairz et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ablation of Fth leads to an increase in the labile iron pool (LIP) within the cell contributing to increased oxidative stress and cell death, though when cells are stimulated the increased availability of Fe2+ iron enhances proliferative capacity before ultimately undergoing cell death.

    “Ablation of Fth leads to an increase in the labile iron pool (LIP) within the cell contributing to increased oxidative stress and cell death, though when cells are stimulated the increased availability of Fe2+ iron enhances proliferative capacity before ultimately undergoing cell death, possibly due to proliferating cells using up the excess iron (Vanoaica et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vanoaica et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Degeneration of cells in the brain results in the deposition of iron in the extracellular space, which then induces waves of oxidative stress (via Fenton chemistry) in these brain regions.

    “However, degeneration of cells in the brain also result in the deposition of iron in the extracellular space, which then induces waves of oxidative stress (via Fenton chemistry) in these brain regions (Craelius et al., 1982; Bagnato et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Craelius et al., 1982

      Not checked in the free run.

    • cites Bagnato et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    Unlike neutrophils which release MPO into the phagosome, eosinophils release their EPX-containing granules extracellularly to kill parasites to which they are attached.

    “However, unlike neutrophils which release MPO into the phagosome, eosinophils release their EPX-containing granules extracellularly to kill parasites to which they are attached (Acharya and Ackerman, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Acharya and Ackerman, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with iron-overload in beta-thalassemia major have decreased CD4+ T cells but increased CD8+ T cell numbers.

    “Patients with iron-overload in beta-thalassemia major have decreased CD4+ T cells but increased CD8+ T cell numbers (Porto and De Sousa, 2007), while patients suffering from hereditary hemochromatosis (HH) have apparently normal CD4+ and reduced CD8+ numbers, with the latter displaying a more “effector” phenotype, suggesting again that increased intracellular iron availability may have hyper-prol”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Porto and De Sousa, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the tumor microenvironment, M2 TAMs which are iron-releasing support tumor growth while M1 iron-retaining limit tumor progression.

    “However, in the context of the tumor microenvironment (TME), the situation is quite complicated as M2 TAMs (tumor-infiltrating macrophages) which are “iron-releasing” will support tumor growth while M1 “iron-retaining” limit tumor progression (Jung et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jung et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRAMP1 acts as a transporter for divalent metals, including iron, and promotes iron export from the phagolysosome and then from the cytoplasm by induction of FPN expression.

    “NRAMP1 acts as a transporter for divalent metals, including iron, and promotes iron export from the phagolyosome and then from the cytoplasm by induction of FPN expression (Nairz et al., 2007; Lim et al., 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nairz et al., 2007 source

      Not checked in the free run.

    • cites Lim et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M2 macrophages promote iron recirculation and aid in tissue healing, a process which requires large amounts of iron to rebuild damaged tissue.

    “This allows the M2 macrophages to promote iron recirculation and aid in tissue healing, a process which requires large amount of iron to rebuild damaged tissue (Recalcati et al., 2010a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Recalcati et al., 2010a

      Not checked in the free run.

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

    Premisecitation

    Eosinophils have a homolog of MPO called eosinophil peroxidase (EPX) which shares ~70% similarity at the amino acid level with neutrophilic MPO.

    “Interestingly, eosinophils have a homolog of MPO called eosinophil peroxidase (EPX) which shares ~70% similarity at the amino acid level with neutrophilic MPO (Ten et al., 1989).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ten et al., 1989

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HO-1 exerts cytoprotective effects by reducing the pro-oxidative activity of heme and by re-programming metabolic traits, thereby limiting tissue damage in inflammatory processes, including sepsis.

    “Thus, HO-1 exerts cytoprotective effects by reducing the pro-oxidative activity of heme and by re-programming metabolic traits, thereby limiting tissue damage in the course of inflammatory processes, including sepsis (Gozzelino et al., 2010; Weis et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gozzelino et al., 2010 source

      Not checked in the free run.

    • cites Weis et al., 2017 source

      Not checked in the free run.

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

    Premisecitation

    Microglial dystrophy has been observed in Alzheimer's brains as well as aged brains.

    “Such microglial dystrophy has been observed in Alzheimer's brains as well as aged brains (Lopes et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lopes et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within a minute of T cell receptor (TCR) engagement, surface TFR is upregulated from endosomal compartments and localized to the immunological synapse, necessary for full T cell activation.

    “Indeed within a minute of T cell receptor (TCR) engagement, surface TFR is upregulated from endosomal compartments and is localized to the immunological synapse (IS), the receptor-filled contact area between an antigen-presenting cell and a T cell, necessary for full T cell activation (Batista et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Batista et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lung cancer, iron-laden TAMs enhance production of ROS and pro-inflammatory cytokines (TNFα and IL-6) and directly kill tumor cells.

    “In lung cancer for example, iron-laden TAMs have been demonstrated to enhance production of ROS and pro-inflammatory cytokines (TNFα and IL-6) and to directly kill tumor cells (da Silva et al., 2017), prompting the exciting possibility of delivering iron to TAMs as a simple adjuvant therapeutic strategy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites da Silva et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme scavenging proteins such as hemopexin can bind free heme, thus clearing it from the circulation and delivering it to cells.

    “Heme scavenging proteins such as hemopexin can bind free heme, thus clearing it from the circulation and delivering it to cells (Smith et al., 1988).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Smith et al., 1988 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which enhances antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine IL-10.

    “In contrast, M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which has been shown to enhance antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine, IL-10 (Weiss et al., 1994; Mulero et al., 2002; Fritsch”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Weiss et al., 1994 source

      Not checked in the free run.

    • cites Mulero et al., 2002 source

      Not checked in the free run.

    • cites Fritsche et al., 2008 source

      Not checked in the free run.

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

    Premisecitation

    GCH1 is the rate-limiting enzyme for BH4 biosynthesis.

    “GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme for BH4 biosynthesis (Werner et al., 2011; Figure 4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Werner et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A link between iron homeostasis and global DNA methylation status has been suggested, by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.

    “Levels of intracellular iron were increased significantly in SLE CD4+ T cells compared to healthy controls and the researchers suggest a link between iron homeostasis and global DNA methylation status (Zhao et al., 2018), by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhao et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GM-CSF is essential for the development and progression of EAE; mice deficient in GM-CSF are resistant to EAE induction, and blockade of GM-CSF in wild-type mice suppresses ongoing disease.

    “GM-CSF is essential for the development and progression of EAE. Mice deficient in GM-CSF are resistant to EAE induction, and blockade of GM-CSF in wild-type mice suppresses ongoing disease (McQualter et al., 2001; Codarri et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McQualter et al., 2001 source

      Not checked in the free run.

    • cites Codarri et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    BH4 deficiency affects iron metabolism and the cell compensates by trying to increase Fe2+ levels in the mitochondria.

    “suggesting that BH4 deficiency affects iron metabolism and the cell compensates by trying to increase Fe2+ levels in the mitochondria.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Ferroptosis is an iron-dependent oxidative form of cell death associated with increased lipid peroxidation.

    “Ferroptosis is an iron-dependent oxidative form of cell death associated with increased lipid peroxidation (Xie et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xie et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron protects PCBP1, an RNA binding protein which stabilizes GMCSF mRNA, from caspase-mediated proteolysis, leading to enhanced GMCSF production when iron levels are high within the T cell to drive inflammation.

    “It was demonstrated that iron protects PCBP1 (Poly(RC)-binding protein 1), an RNA binding protein which stabilizes GMCSF mRNA, from caspase-mediated proteolysis thus leading to enhanced GMCSF production when iron levels are high within the T cell to drive inflammation (Wang et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al., 2018 source

      Not checked in the free run.

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

    Premisecitation

    Through these enzymes, BH4 is required for nitric oxide production, metabolism of ether lipids, phenylalanine catabolism, and synthesis of amine neurotransmitters norepinephrine, epinephrine, serotonin, and dopamine.

    “Through these enzymes, BH4 is required for nitric oxide (NO) production, metabolism of ether lipids, phenylalanine catabolism, and synthesis of the amine neurotransmitters norepinephrine, epinephrine, serotonin, and dopamine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Werner et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferroptosis can be blocked with iron chelators but not with inhibitors of apoptosis and necroptosis.

    “Moreover, ferroptosis can be blocked with iron chelators but not with inhibitors of apoptosis and necroptosis (Xie et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xie et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A common phenotype of defective Fe-S biogenesis is mitochondrial iron loading, resulting in mitochondrial dysfunction and oxidative stress.

    “A common phenotype of defective Fe-S biogenesis is mitochondrial iron loading, resulting in mitochondrial dysfunction and oxidative stress (Reeve et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Reeve et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients suffering from hereditary hemochromatosis (HH) have apparently normal CD4+ and reduced CD8+ numbers, with the latter displaying a more effector phenotype, suggesting that increased intracellular iron availability may have hyper-proliferative effects in T cells, although this may depend on which oxidation form of Fe is available.

    “while patients suffering from hereditary hemochromatosis (HH) have apparently normal CD4+ and reduced CD8+ numbers, with the latter displaying a more “effector” phenotype, suggesting again that increased intracellular iron availability may have hyper-proliferative effects in T cells, although this may well-depend on which oxidation form of Fe is available (Costa et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Costa et al., 2015 source

      Not checked in the free run.

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

    Premisecitation

    Sulfasalazine has been used for decades to treat autoimmune inflammatory bowel disease and psoriatic arthritis.

    “Intriguingly, sulfasalazine, a drug used for decades to treat autoimmune inflammatory bowel disease (IBD) and psoriatic arthritis (Gupta et al., 1990), is now recognized as targeting the BH4 pathway by inhibiting SPR (Haruki et al., 2013), in addition to other targets, such as NFκB (Wahl et al., 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gupta et al., 1990 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFNγ enhances expression of cellular iron-regulating genes such as HO-1 but also reduces the iron-exporting gene ferroportin.

    “IFNγ has a strong regulatory role in iron homeostasis as it enhances the expression of cellular iron-regulating genes such as HO-1 but also reduces the iron-exporting gene ferroportin (Ludwiczek et al., 2003; Nairz et al., 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ludwiczek et al., 2003 source

      Not checked in the free run.

    • cites Nairz et al., 2015 source

      Not checked in the free run.

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

    Premisecitation

    Sulfasalazine also targets NFκB.

    “Intriguingly, sulfasalazine, a drug used for decades to treat autoimmune inflammatory bowel disease (IBD) and psoriatic arthritis (Gupta et al., 1990), is now recognized as targeting the BH4 pathway by inhibiting SPR (Haruki et al., 2013), in addition to other targets, such as NFκB (Wahl et al., 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wahl et al., 1998 source

      Not checked in the free run.

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

    Premisecitation

    High doses of sulfasalazine are associated with RBC abnormalities.

    “Interestingly, high doses of sulfasalazine are associated with RBC abnormalities (Pounder et al., 1975).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pounder et al., 1975 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Targeting the BH4 pathway offers a novel therapeutic and new mode-of-action opportunity to control T cell proliferation, and in this way help to control autoimmunity or enhance anti-cancer immunity.

    “Targeting this pathway offers a novel therapeutic and new mode-of-action opportunity to control T cell proliferation, and in this way help to control autoimmunity or enhance anti-cancer immunity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cronin et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A general decrease in Fe3+ reduction resulting in scarcity of Fe2+ and increase of Fe3+ would affect many aspects of cellular metabolism, contributing to reduced T cell proliferation observed with BH4-deficiency.

    “A general decrease in Fe3+ reduction resulting in a scarcity of Fe2+ and increase of Fe3+ would affect many aspects of cellular metabolism (Volani et al., 2017) which contribute to the reduced T cell proliferation observed with BH4-deficiency.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Volani et al., 2017 source

      Not checked in the free run.

    • Rests on an assumption: Fe2+ is needed for metalloproteins like cytochrome-C to function optimally, for Fe-S cluster biogenesis, which are essential for complex I and II activity of the ETC, and for heme production.
86 of 86

  • The paper relies on this without support.

    Iron is essential to almost all organisms.

    “Iron is one of the most abundant elements on Earth and essential to almost all organisms.”

  • The paper relies on this without support.

    Normal physiology is a balance between reactive oxygen species and antioxidants, with antioxidants maintaining useful ROS levels while minimizing bystander damage.

    “Normal physiology is a balance between the two: antioxidants maintain levels of ROS that permit them to perform useful biological functions, such as neutrophil-mediated killing of phagocytosed bacteria or enhanced T cell proliferation after TCR stimulation, while minimizing by-stander damage.”

  • The paper relies on this without support.

    Iron is essential for many physiological processes including erythropoiesis, immune function, host defense, DNA replication and repair, mitochondrial function including OXPHOS, and enzymatic reactions requiring iron as a cofactor.

    “Iron is essential for many physiological processes in the body including erythropoiesis, immune function and host defense, as well as essential cellular activities such as DNA replication and repair, mitochondrial function including OXPHOS and enzymatic reactions which require iron as a cofactor.”

  • The paper relies on this without support.

    There exists no effective excretion mechanism for iron surplus.

    “As there exists no effective excretion mechanism for iron surplus, iron is stored in parenchymal organs, mainly the liver.”

  • The paper relies on this without support.

    Intracellular iron levels are tightly controlled.

    “Similar to systemic iron levels in the bloodstream, the intracellular iron levels are tightly controlled.”

  • The paper relies on this without support.

    The iron cycle is present in almost all cells of the body.

    “The iron cycle is present in almost all cells of the body, and so the regulatory networks described above are also essential to the cells of the immune system.”

  • The paper relies on this without support.

    Both iron deficiency and iron excess can influence both the innate and adaptive arms of the immune system.

    “Both iron deficiency and iron excess can influence both the innate and adaptive arms of the immune system.”

  • The paper relies on this without support.

    Iron is essential for cell division.

    “Notably, as iron is so essential for cell division, one of the earliest tasks of invading pathogens is to capture host iron in the circulation to aid their own growth and expansion.”

  • The paper relies on this without support.

    Restricting free iron is a first line of defense against invading pathogens.

    “Therefore, restricting free iron is a first line of defense against invading pathogens.”

  • The paper relies on this without support.

    Hepcidin promotes intracellular iron retention, thus restricting its availability for pathogens in the circulation.

    “Hepcidin is an important gatekeeper which promotes intracellular iron retention thus restricting its availability for pathogens in the circulation.”

  • The paper relies on this without support.

    The increase of hepcidin within hours of an infection or inflammatory insult results in a dramatic reduction of plasma iron levels.

    “The increase of hepcidin within hours of an infection or inflammatory insult, results in a dramatic reduction of plasma iron levels.”

  • The paper relies on this without support.

    Iron is essential for ferroptosis because Fe2+ converts hydrogen peroxide produced by mitochondrial respiration into hydroxyl radical through Fenton chemistry, which then takes electrons from lipids resulting in lipid peroxidation and ferroptosis.

    “Iron is essential for the process of ferroptosis as free divalent iron (Fe2+) converts the hydrogen peroxide (H2O2) produced by mitochondrial respiration into the toxic free hydroxyl radical (OH•) through Fenton chemistry which then “takes” electrons from lipids resulting in lipid peroxidation and ferroptosis.”

  • The paper relies on this without support.

    Iron homeostasis, its regulation through uptake, use, storage and export, influences the activity of metabolic pathways to couple the activation, growth and survival of T cells.

    “Iron homeostasis, its regulation through uptake, use, storage and export, influences the activity of metabolic pathways to couple the activation, growth and survival of T cells.”

  • The paper relies on this without support.

    Fe2+ is needed for metalloproteins like cytochrome-C to function optimally, for Fe-S cluster biogenesis, which are essential for complex I and II activity of the ETC, and for heme production.

    “Fe2+ is not only needed for metalloproteins like cytochrome-C to function optimally but also for Fe-S cluster biogenesis, which are essential for complex I and II activity of the ETC, and heme production (Figure 4).”
14 of 14

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?

  • The interactions of iron homeostasis, infections and immune pathways are active areas of investigation that expand from basic research in immunometabolism to clinical studies in infectious diseases.

    “The interactions of iron homeostasis, infections and immune pathways are active areas of investigations that expand from basic research in immunometabolism to clinical studies in infectious diseases (Cronin et al., 2020).”

    From Iron in infection and immunity (2020) · cites this paper as Cronin et al., 2020

  • iNOS produces large amounts of •NO as a defense mechanism, is synthesized by several cell types in response to cytokine release, and is an important factor in the body's response to parasite attack, bacterial infection, and tumor growth.

    “iNOS produces large amounts of •NO as a defense mechanism and is synthesized by several cell types in response to cytokine release and is an important factor in the body’s response to parasite attack, bacterial infection, and tumor growth [109].”

    From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [109]

Cites

Flagged first, then by citations

6 of the 214 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M.
Affiliations
  • Institute of Molecular Biotechnology (AT)
  • Boston Children's Hospital (US)
Corresponding author
Penninger, Josef M.
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
Frontiers Media SA
Published
2019-11-22
Volume
6
Pages
116-116
ISSN
2296-889X (ISSN-L)
DOI
10.3389/fmolb.2019.00116
PMC
PMC6883604
OpenAlex
W2991203943
Cited by
299
References
214
Citations by year
2026: 28 · 2025: 50 · 2024: 49 · 2023: 45 · 2022: 56 · 2021: 47 · 2020: 24
FWCI
5.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
iron metabolism, immunometabolism, immune cell metabolism, iron bioavailability, immune cell homeostasis, inflammation, autoimmunity, tumor immunology, metabolic reprogramming, immune-related diseases

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review