CoChat
Sign Up
Cited by 108Iron Metabolism and DisordersBacterial Genetics and BiotechnologySalmonella and Campylobacter epidemiology

Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection

Open access
Nairz, Manfred, Ferring-Appel, Dunja, Casarrubea, Daniela, Sonnweber, Thomas, Viatte, Lydie, Schroll, Andrea, Haschka, David, Fang, Ferric C. +3 more·2015·Cell Host & Microbe
DOI 10.1016/j.chom.2015.06.017PMC PMC4666941
Open this paper in CoChat — free accountOpen PDF

Abstract

Macrophages are essential for systemic iron recycling, and also control iron availability to pathogens. Iron metabolism in mammalian cells is orchestrated posttranscriptionally by iron-regulatory proteins (IRP)-1 and -2. Here, we generated mice with selective and combined ablation of both IRPs in macrophages to investigate the role of IRPs in controlling iron availability. These animals are hyperferritinemic but otherwise display normal clinical iron parameters. However, mutant mice rapidly succumb to systemic infection with Salmonella Typhimurium, a pathogenic bacterium that multiplies within macrophages, with increased bacterial burdens in liver and spleen. Ex vivo infection experiments indicate that IRP function restricts bacterial access to iron via the EntC and Feo bacterial iron-acquisition systems. Further, IRPs contain Salmonella by promoting the induction of lipocalin 2, a host antimicrobial factor that inhibits bacterial uptake of iron-laden siderophores, and by suppressing the ferritin iron pool. This work reveals the importance of the IRPs in innate immunity.

Integrity signals

Registry

Crossref · 10.1016/j.chom.2015.06.017

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    IRP loss does not prevent hepcidin from degrading FPN.

    “Importantly, IRP deficiency does not interfere with hepcidin-mediated degradation of FPN (Figure 1D).”
    Quote in the paperSubstantial claim
  • Findingcitation

    IrpLyzCre(+) mice have markedly higher plasma ferritin.

    “Of note, IrpLyzCre(+) mice display a marked increase in plasma ferritin concentration (Figure 1E), as predicted for animals with augmented macrophage ferritin expression (Cohen et al., 2010).”
    • Also stated in: § Abstract · plain
      “These animals are hyperferritinemic but otherwise display normal clinical iron parameters.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cohen et al., 2010 source

      Not checked in the free run.

  • Findingown data

    Since IRP loss raises basal FPN, more hepcidin is needed to suppress FPN.

    “However, because basal FPN expression is elevated in IRP deficiency, higher doses of hepcidin are required to suppress FPN.”
    Quote in the paperSubstantial claim
  • Findingown data

    The triple sit feo entC S.Tm mutant grows less than wild-type bacteria.

    “Proliferation of this mutant is expectedly reduced compared to wild-type bacteria (Figure 4A).”
    Quote in the paperSubstantial claim
  • Findingown data

    IRP loss does not significantly reduce hypoferremia caused by aseptic inflammatory stimuli in mice.

    “Although IRP deficiency antagonizes hepcidin-mediated suppression of FPN (Figure 1D), it does not significantly mitigate the hypoferremia induced by aseptic inflammatory stimuli in mice (Figure S2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingcitation

    Removing both IRPs together strongly increases FPN, FTH1, and FTL1 and lowers TFR1 protein and mRNA.

    “the simultaneous ablation of both IRPs causes a marked increase in FPN, FTH1, and FTL1 expression (Figure 1A, left), most likely due to translational derepression of the corresponding mRNAs (Galy et al., 2013) and to a minor extent to increased mRNA expression (Figure 1A, right); double IRP deficiency expectedly decreases TFR1 protein and mRNA levels (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Galy et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Loss of IRP1 alone does not significantly change IRP target genes, while loss of IRP2 alone slightly raises FTL1.

    “IRP-target genes are not significantly affected by single IRP1 deficiency, and IRP2 disruption alone causes a minor increase in FTL1 (Figure 1A, left).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In control BMDMs, DFO raises TFR1 mRNA and protein and slightly lowers FPN protein; hemin lowers TFR1 and raises FTL1, FTH1, and FPN.

    “In IrpLyzCre(−) BMDMs, iron chelation by deferoxamine (DFO) augments TFR1 mRNA and protein levels and slightly decreases FPN protein expression; the expected suppression of ferritin could not be observed because of already low basal expression. Opposite to DFO, the iron source hemin suppresses TFR1 and stimulates FTL1, FTH1, and FPN at the protein and less so at the mRNA level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Peritoneal macrophages from IrpLyzCre(+) mice have high ferritin and low TFR1.

    “Similar to BMDMs, elicited peritoneal macrophages (PMΦ) from IrpLyzCre(+) mice display high ferritin and low TFR1 expression (Figure 1B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    BMDMs from IrpLyzCre(+) mice show efficient IRP1 and/or IRP2 loss by Western blot, with some residual IRP likely from mosaic Lyz2-Cre activity.

    “Western blotting shows efficient ablation of IRP1 and/or IRP2 in BMDMs, with residual amounts of IRP (Figure 1A, left) possibly reflecting mosaic activity of the Lyz2-Cre strain (Tuckerman et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tuckerman et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    IRP-deficient BMDMs still lower TFR1 further when iron-loaded and slightly raise it when iron-chelated.

    “IRP-deficient BMDMs still respond to iron fluctuation with further reduction of TFR1 upon iron loading (TFR1 mRNA ratio hemin/non-treated: IrpLyzCre(−), 0.18±0.04; IrpLyzCre(+), 0.34 ±0.08) and a slight increase upon iron chelation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IrpLyzCre(+) mice are born at Mendelian ratios and look similar to control littermates.

    “Aco1flox/flox,Ireb2flox/flox,Lyz2+/Cre mice (designated IrpLyzCre(+)) are born at Mendelian ratio and do not overtly differ from Aco1flox/flox,Ireb2flox/flox,Lyz2+/+control littermates (IrpLyzCre(−)).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In vivo, IRP loss raises ferritin posttranscriptionally in liver and spleen macrophages; FPN rises in liver but not spleen.

    “Similar to primary macrophage cultures (Figure 1), IRP ablation increases ferritin expression posttranscriptionally in vivo, both in liver and spleen macrophages (Supplementary figure 1 available online); FPN expression is augmented in liver (Figure S1A) but not in spleen (Figure S1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In IrpLyzCre(+) cells, FTL1 protein stays unresponsive to DFO and rises slightly with hemin, along with FTL1 mRNA; hemin also raises FPN mRNA and markedly raises FPN protein.

    “FTL1 protein expression remains unresponsive to DFO in IrpLyzCre(+) cells, and is slightly increased by hemin (Figure 1C, left) accompanied by an increase of the FTL1 mRNA (Figure 1C, right, the same is observed for FTH1); FPN mRNA stimulation by hemin (Figure 1C, right) is accompanied by a marked FPN upregulation at the protein level (Figure 1C, left).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The antibacterial defect of IrpLyzCre(+) macrophages remains with sitABCD-deficient S.Tm, disappears with entC-deficient bacteria, and is intermediate with Feo disruption.

    “While the antimicrobial deficit of IrpLyzCre(+) macrophages is evident with S.Tm lacking sitABCD, it is abolished when the bacteria lack the siderophore iron uptake pathway (entC) (Figure 4C); disruption of the Feo system has an intermediate effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adding exogenous LCN2 fully reverses the antibacterial defect of IrpLyzCre(+) macrophages; blocking endogenous LCN2 has only a slight effect, and LCN2 inhibition in control macrophages partly mimics the IRP-null defect.

    “The anti-bacterial deficit of IrpLyzCre(+) macrophages is fully reverted by exogenous addition of LCN2 (Figure 4D, left), and is only slightly affected by inhibition of endogenous LCN2 (Figure 4D, right); LCN2 inhibition in IrpLyzCre(−) macrophages at least partially phenocopies the anti-bacterial deficit of IRP-null cells (Figure 4D, right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IRP loss does not change macrophage ROS production after S.Tm infection or uptake of heat-killed fluorescent S.Tm.

    “Of note, IRP ablation does not alter the capacity of macrophages to produce reactive oxygen species upon infection with S.Tm (Figure S3A), nor the engulfment of fluorescently-labeled heat-killed S.Tm particles (Figure S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Bacteria take up about threefold more 59Fe when infecting IRP-deficient versus control macrophages; uptake by the triple sit feo entC mutant is lower and unaffected by host IRP status.

    “Likewise, while microbial 59Fe uptake is ~3-fold higher when bacteria infect IRP-deficient versus control macrophages (Figure 4B), iron acquisition by the sit feo entC S.Tm mutant is diminished and unaffected by the IRP status of the host cell (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    IrpLyzCre(+) mice develop normally, are fertile, and show no illness in standard laboratory housing.

    “Surprisingly, IrpLyzCre(+) mice develop normally, are viable and fertile, and show no sign of illness when maintained in a standard laboratory environment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under standard laboratory conditions, IRP loss in MPS cells does not detectably change plasma iron, transferrin saturation, hematological parameters, or tissue iron stores.

    “Although ferritin and FPN mediate, respectively, macrophage iron retention and export, misregulation of these critical iron management molecules in MPS cells has no detectable impact on plasma iron levels and transferrin saturation values (Figure 1E); hematological parameters and tissue iron stores are also unaffected (Table S1).”
    • Also stated in: § Role of IRPs in macrophage and body iron homeostasis · plain
      “Hence, IRPs control key iron handling molecules in MPS macrophages in vivo but are dispensable for maintaining the body iron balance under standard laboratory conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mice lacking macrophage IRPs survive like wild-type littermates when infected with entC or feo mutants, but are more vulnerable to sitABCD mutant infection.

    “In line with those results, we find that mice with macrophage IRP deficiency display the same survival as wild-type littermates when infected with entC or feo mutant bacteria, respectively, but remain significantly more vulnerable to infection with the sitABCD mutant strain (Figure S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Exogenous TNFA and/or IL6 increase killing by both IrpLyzCre(+) and IrpLyzCre(−) cells but do not rescue IRP deficiency.

    “In contrast to LCN2, exogenous addition of TNFA and/or IL6, whose induction is also impaired in IrpLyzCre(+) macrophages (Figure 3D), enhances the bactericidal activity of both IrpLyzCre(+) and IrpLyzCre(−) cells but does not rescue IRP deficiency (Fig. S4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    S.Tm obtains ferrous iron through SitABCD and Feo and ferric iron through siderophores.

    “S.Tm acquires elemental ferrous iron via the SitABCD and Feo systems and takes up ferric iron with the help of siderophores (Osman and Cavet, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Osman and Cavet, 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both IRPs and hepcidin set macrophage FPN levels and thus iron export capacity.

    “This shows that both IRPs and hepcidin are important to set FPN levels and hence the iron export capacity of macrophages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LCN2 is an infection-induced host antimicrobial that blocks bacterial uptake of iron-loaded siderophores.

    “Lipocalin 2 (LCN2) is a host antimicrobial factor induced upon infection that inhibits bacterial uptake of iron-laden siderophores (Flo et al., 2004, Raffatellu et al., 2009, Deriu et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Flo et al., 2004 source

      Not checked in the free run.

    • cites Raffatellu et al., 2009 source

      Not checked in the free run.

    • cites Deriu et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In mammalian cells, IRP1 and IRP2 control iron metabolism after transcription.

    “Iron metabolism in mammalian cells is orchestrated post-transcriptionally by iron-regulatory proteins (IRP)-1 and -2.”
    • Also stated in: § Introduction · plain
      “iron metabolism is also regulated cellularly by the iron regulatory proteins (IRP)-1 and -2 (a.k.a. ACO1 and IREB2, respectively) (Kühn, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kühn, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking IRPs completely in hepatocytes or duodenal enterocytes die early after birth, showing IRPs are needed for organismal survival.

    “Earlier work investigating mice with complete IRP deficiency in hepatocytes or duodenal enterocytes, respectively, had shown early post-natal death in both cases, reflecting essential functions of the IRPs for organismal survival (Galy et al., 2008, 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Galy et al., 2008 source

      Not checked in the free run.

    • cites Galy et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Macrophage ferritin is mainly controlled by IRP-dependent translation, while FPN levels depend on both IRP-dependent and IRP-independent pathways.

    “These data indicate that ferritin regulation in macrophages is dominated by IRP-dependent control of ferritin translation, whereas FPN levels are set through both IRP-dependent and IRP-independent regulatory pathways.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    S.Tm survives inside MPS cells such as spleen and liver macrophages, causes systemic disease in mice, and is known to require iron.

    “This Gram-negative bacterium persists within MPS cells, including spleen and liver macrophages, it causes systemic disease in mice (Vazquez-Torres et al., 1999, 2004), and its dependence on iron is well established (Nairz et al., 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Vazquez-Torres et al., 1999 source

      Not checked in the free run.

    • cites Vazquez-Torres et al., 2004 source

      Not checked in the free run.

    • cites Nairz et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages carry out systemic iron recycling and regulate iron availability to pathogens.

    “Macrophages are essential for systemic iron recycling, and also control iron availability to pathogens.”
    • Also stated in: § Introduction · plain
      “Macrophage iron metabolism is thus critical both for securing body iron sufficiency and immunity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ganz, 2013 source

      Not checked in the free run.

    • cites Drakesmith and Prentice, 2012 source

      Not checked in the free run.

    • cites Nairz et al., 2014 source

      Not checked in the free run.

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

    Premisecitation

    Macrophages need HIF2α for cytokine induction.

    “HIF2α is required for cytokine induction in macrophages (Imtiyaz et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Imtiyaz et al., 2010 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    By binding IREs on target mRNAs, IRPs posttranscriptionally regulate genes for TFR1, FTH1, FTL1, and FPN.

    “IRPs respond to changes in cellular iron levels and in turn enact posttranscriptional regulation of key iron metabolism genes via their interaction with cis-regulatory iron responsive elements (IRE) present on target mRNAs, including those encoding the transferrin receptor (TFR1), the ferritin-H (FTH1) and –L (FTL1) iron storage proteins, and the iron exporter FPN.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kühn, 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Iron affects immune responses through several mechanisms.

    “Iron indeed modulates the immune response in multiple ways.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Nairz et al., 2014 source

      Not checked in the free run.

    • cites Wang et al., 2009

      Not checked in the free run.

    • cites Zhang et al., 2011 source

      Not checked in the free run.

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

    Study design and conductnone given

    Animal handling followed approved EMBL, Medical University of Innsbruck, and Austrian Ministry guidelines.

    “Animal handling was in accordance with approved guidelines from the EMBL, the Medical University of Innsbruck Animal ethics committee, and the Austrian Ministry for Science and Education (approvals: BMWF-66.011/0151-II/3b/2011 and BMWFW-66.011/0111-WF/V/3b/2014).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control animals for all IrpLyzCre(+) studies were IrpLyzCre(−) littermates.

    “For all studies of IrpLyzCre(+) mice, control animals consisted of IrpLyzCre(−) littermates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IRPs block siderophore-mediated bacterial iron uptake and limit Feo-mediated but not SitABCD-mediated elemental iron acquisition.

    “IRPs thus restrain siderophore-mediated bacterial iron uptake, and limit elemental iron acquisition via the Feo but not the SitABCD system.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Mouse lines were backcrossed to C57BL/6 for at least ten generations.

    “All mouse lines were backcrossed to C57BL/6 animals for at least 10 generations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Two underlying mechanisms emerge: IRP promotion of LCN2 synthesis and IRP suppression of the ferritin iron pool, which together restrict S.Tm iron acquisition and growth.

    “Although additional mechanisms may contribute, the restriction of S.Tm iron acquisition and proliferation by promotion of LCN2 synthesis and suppression of the ferritin iron pool emerge as underlying mechanisms.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Unless specified, male mice aged 10 to 12 weeks were used.

    “Unless specified, 10 to 12 week-old male mice were used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Iron accumulates in IrpLyzCre(+) cells despite lower TFR1 and higher FPN, possibly because it is sequestered in excess ferritin.

    “Iron loading in IrpLyzCre(+) cells occurs in spite of reduction of the TFR1 iron uptake molecule and stimulation of the FPN iron exporter (Figure 1), and could possibly reflect sequestration of the metal into the overabundant ferritin (Galy et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Galy et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    IRPs are required for adequate host LCN2 production and for limiting siderophore-mediated iron uptake.

    “First, IRPs are needed for sufficient host LCN2 production and restriction of siderophore-mediated iron uptake”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Statistical testing used two-tailed Student's t-test, one-way ANOVA with Bonferroni, log-rank tests, and a p<0.05 threshold.

    “Differences between two mean values were evaluated by two-tailed Student’s t-test (data were log-transformed for the comparison of bacterial loads and mRNA levels of immune response genes). Multiple groups were compared by one-way ANOVA with Bonferroni’s post hoc analysis. To compare survival curves the log-rank test was used. A p value < 0.05 was considered significant.”
    Quote in the paperSubstantial claim
37 of 37

  • The paper relies on this without support.

    Before this study, how macrophage IRPs contribute to body iron recycling and immunity was unknown.

    “The role of macrophage IRPs in body iron recycling and immunity is not known.”

  • The paper relies on this without support.

    Ferritin and ferroportin mediate iron retention and export in macrophages, respectively.

    “Although ferritin and FPN mediate, respectively, macrophage iron retention and export, misregulation of these critical iron management molecules in MPS cells has no detectable impact on plasma iron levels and transferrin saturation values (Figure 1E); hematological parameters and tissue iron stores are also unaffected (Table S1).”
2 of 2

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?

  • Lipocalin-2 (NGAL), secreted by neutrophils, macrophages and epithelia in response to infection, binds to siderophores such as enterobactin and prevents bacterial iron acquisition by this route.

    “For example, lipocalin-2 or neutrophil gelatinase-associated lipocalin (NGAL), a protein secreted by neutrophils, macrophages and epithelia in response to infection binds to siderophores, such as enterobactin, and prevents bacterial iron acquisition by this route.”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2015

  • Mice lacking lipocalin-2 exhibit increased mortality from infection with siderophore-expressing bacteria such as E. coli, demonstrating the anti-microbial relevance of this bacterial iron withholding system.

    “Mice lacking lipocalin-2 exhibit increased mortality from infection with siderophore-expressing bacteria, such as E. coli, demonstrating the anti-microbial relevance of this bacterial iron withholding system (Flo et al., 2004; Nairz et al., 2015).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2015

  • Neutrophils secrete lipocalin-2 to interfere with bacteria scavenging host iron from the bloodstream.

    “Neutrophils, as noted above, secrete lipocalin-2 to interfere with bacteria scavenging host iron from the bloodstream (Flo et al., 2004; Nairz et al., 2015).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2015

  • 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).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nairz et al., 2015

  • 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.”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [166]

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.

  • Cytokine result points to the nitric-oxide figure panel

    Minor

    The text identifies Figure 3C as showing cytokine induction and Figure 3D as showing nitric oxide production. It later cites Figure 3D for impaired TNFA and IL6 induction.

1 of 1

Cites

Flagged first, then by citations

1 of the 37 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Nairz, M., Ferring-Appel, D., Casarrubea, D., Sonnweber, T., Viatte, L., Schroll, A., Haschka, D., Fang, F. C., Hentze, M. W., Weiss, G., & Galy, B.
Affiliations
  • Innsbruck Medical University (AT)
  • European Molecular Biology Laboratory (DE)
  • University of Washington (US)
Corresponding author
Hentze, Matthias W.
ORCID
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2015-08
Volume
18
Issue
2
Pages
254-261
ISSN
1931-3128 (ISSN-L)
DOI
10.1016/j.chom.2015.06.017
PMC
PMC4666941
OpenAlex
W1620900232
Cited by
103
References
37
Citations by year
2026: 3 · 2025: 5 · 2024: 8 · 2023: 14 · 2022: 9 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 6 · 2017: 10 · 2016: 6 · 2015: 3
FWCI
6.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Host & Microbe (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Bundesministerium für Bildung und Forschung
  • Austrian Science Fund (TRP 188)
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Medizinische Universität Innsbruck
  • Universität Innsbruck
  • National Institutes of Health (AI39557)
  • National Institute of Allergy and Infectious Diseases (AI 39557, R01AI039557, R01AI112640, AI44486, R01AI044486)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
Keywords
iron regulatory proteins, macrophages, Salmonella typhimurium, iron metabolism, iron availability, neutrophil gelatinase-associated lipocalin, siderophore uptake, ferritin, innate immunity, iron recycling
MeSH terms
Animals, Disease Models, Animal, Iron, Liver, Macrophages, Mice, Inbred C57BL, Salmonella Infections, Animal, Salmonella typhimurium, Spleen, Mice, Knockout, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice, Gene Knockout Techniques, Bacterial Load, Disease Resistance

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