The Iron age of host–microbe interactions

In the paper

“However, heme-driven programmed cell death is also suppressed by pharmacologic inhibition of the receptor-interacting serine/threonine kinases 1 (RIPK1), as well as by the deletion of the Ripk3 gene (unpublished observation).”

In the paper

“Mice in which the Fth allele is deleted develop tissue Fe overload and tissue damage succumbing to Plasmodium [107] as well as to polymicrobial infections (unpublished observation).”

What the sources say

• Not checked yetcites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source

In the paper

“It limits the impact of infection on host integrity and fitness without interfering with the host's pathogen burden [14].This is distinct from immunological tolerance [15], and while the two may be functionally linked, they act via distinct mechanisms.”

What the sources say

• Not checked yetcites [14] Caldwell RM, Schafer JF, Compton LE, Patterson FL (1958) Tolerance to cereal leaf rusts. Science 128: 714–715 source
• Not checked yetcites [15] Medawar PB (1961) Immunological tolerance. Nature 189: 14–17 source

In the paper

“Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes.”

In the paper

“While essential to confer host protection against infection, some resistance mechanisms, including those involved in nutritional immunity, can compromise host homeostasis [10].This trade-off is countered by an additional host defense strategy termed as tissue damage control [1,11], which confers disease tolerance to infection [1,12,13].”

What the sources say

• Not checked yetcites [10] Kotas ME, Medzhitov R (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160: 816–827 source
• Not checked yetcites [1] Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335: 936–941 source
• Not checked yetcites [11] Soares MP, Gozzelino R, Weis S (2014) Tissue damage control in disease tolerance. Trends Immunol 35: 483–494 source
• Not checked yetcites [12] Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol 30: 271–294 source
• Not checked yetcites [13] Schneider DS, Ayres JS (2008) Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8: 889–895 source

In the paper

“We will put forward the notion that pathogen class-specific mechanisms regulating Fe metabolism evolved to confer protection against intracellular versus extracellular pathogens.”

In the paper

“This defense strategy, termed nutritional immunity [4], encompasses mechanisms that restrict microbes from accessing iron (Fe) [5][6][7] as well as other trace metals such as zinc, manganese, or copper [8,9].”

• Also stated in: § Introduction · boosted

  “That nutritional immunity is a central defense strategy against infection is supported by the realization that several "infection resistance genes" act via a mechanism controlling host Fe metabolism.”

What the sources say

• Not checked yetcites [4] Weinberg ED (1975) Nutritional immunity. Host's attempt to withold iron from microbial invaders. JAMA 231: 39–41 source
• Not checked yetcites [5] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790: 600–605 source
• Not checked yetcites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

In the paper

“The general principle being that adaptive responses supplying Fe to microbes increase, in most cases, their pathogenicity while those withholding Fe from microbes limit their virulence.”

In the paper

“Regulation of Mø intracellular Fe content by the hepcidin/FPN axis impacts on Mø polarization and presumably therefore resistance to infection [6,66,67].”

What the sources say

• Not checked yetcites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source
• Not checked yetcites [66] Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D, Cairo G (2010) Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 40: 824–835 source
• Not checked yetcites [67] Recalcati S, Locati M, Gammella E, Invernizzi P, Cairo G (2012) Iron levels in polarized macrophages: regulation of immunity and autoimmunity. Autoimmun Rev 11: 883–889 source

In the paper

“This also holds true for polymorphisms in the human HMOX1 gene coding for HO-1, as illustrated for HIV infection [44] and malaria [45,46].”

What the sources say

• Not checked yetcites [44] Seu L, Burt TD, Witte JS, Martin JN, Deeks SG, McCune JM (2012) Variations in the heme oxygenase‐1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV‐infected African‐Americans. Genes Immun 13: 258–267 source
• Not checked yetcites [45] Walther M, De Caul A, Aka P, Njie M, Amambua‐Ngwa A, Walther B, Predazzi IM, Cunnington A, Deininger S, Takem EN et al (2012) HMOX1 gene promoter alleles and high HO‐1 levels are associated with severe malaria in Gambian children. PLoS Pathog 8: e1002579 source
• Not checked yetcites [46] Sambo MR, Trovoada MJ, Benchimol C, Quinhentos V, Gonçalves L, Velosa R, Marques MI, Sepúlveda N, Clark TG, Mustafa S et al (2010) Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in angolan children. PLoS ONE 5: e11141 source

In the paper

“More than 80% of the bioavailable Fe in mammals exists in the form of heme contained in hemoproteins [241].”

What the sources say

• Not checked yetcites [241] Fischer H, Zeile K (1929) Synthese des haematoporphyrins, protoporphyrins und haemins. Justus Liebigs Annalen der Chemie 468: 98–116 source

In the paper

“and repressed in response to: (i) hypoferremia, that is, lower than normal levels of circulating Fe, (ii) anemia, (iii) tissue hypoxia, and (iv) hormones, for example, growth and differentiation factors 15, erythroferrone, platelet-derived growth factor-BB (PDGF-BB) and testosterone [62][63][64][65].”

What the sources say

• Not checked yetcites [62] Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46: 678–684 source
• Not checked yetcites [63] Latour C, Kautz L, Besson‐Fournier C, Island ML, Canonne‐Hergaux F, Loreal O, Ganz T, Coppin H, Roth MP (2014) Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology 59: 683–694 source
• Not checked yetcites [64] Sonnweber T, Nachbaur D, Schroll A, Nairz M, Seifert M, Demetz E, Haschka D, Mitterstiller AM, Kleinsasser A, Burtscher M et al (2014) Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut 63: 1951–1959 source

In the paper

“Moreover, accumulation of intracellular Fe in T cells mitigates the activation, differentiation, and proliferation of T H 1 cells while fostering T H type 2 (T H 2) responses, as illustrated in the context of Candida albicans infection in mice [69,71].”

What the sources say

• Not checked yetcites [69] Mencacci A, Cenci E, Boelaert JR, Bucci P, Mosci P, Fe d'Ostiani C, Bistoni F, Romani L (1997) Iron overload alters innate and T helper cell responses to Candida albicans in mice. J Infect Dis 175: 1467–1476 source
• Not checked yetcites [71] Omara FO, Blakley BR (1994) The effects of iron deficiency and iron overload on cell‐mediated immunity in the mouse. Br J Nutr 72: 899–909 source

In the paper

“Both NOX2/gp91 phox and iNOS/ NOS2 are prototypical hemoproteins that use Fe-heme to catalyze the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively [76].”

What the sources say

• Not checked yetcites [76] Nathan C, Shiloh MU (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA 97: 8841–8848 source

In the paper

“The physiologic relevance of this mechanism was recently underpinned by the description of hepcidin-independent hypoferremia in mouse models of inflammation [87], and the fact that tumor necrosis factor (TNF) causes sustained hypoferremia in mice, irrespective of hepcidin [88].”

What the sources say

• Not checked yetcites [87] Guida C, Altamura S, Klein FA, Galy B, Boutros M, Ulmer AJ, Hentze MW, Muckenthaler MU (2015) A novel inflammatory pathway mediating rapid hepcidin‐independent hypoferremia. Blood 125: 2265–2275 source
• Not checked yetcites [88] Alvarez‐Hernandez X, Liceaga J, McKay IC, Brock JH (1989) Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest 61: 319–322

In the paper

“Hepcidin expression is regulated mainly at the level of transcription of the hepcidin (HAMP) gene, being induced in response to: (i) hyperferremia, that is, higher than normal levels of circulating Fe, (ii) cytokines, for example, interleukin (IL)-1, IL-6, and IL-22, or (iii) recognition of bacterial lipopolysaccharide by Toll-like receptor 4 (TLR4) [59][60][61]”

What the sources say

• Not checked yetcites [59] Loreal O, Cavey T, Bardou‐Jacquet E, Guggenbuhl P, Ropert M, Brissot P (2014) Iron, hepcidin, and the metal connection. Front Pharmacol 5: 128
• Not checked yetcites [60] Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA, Ho LP, Townsend AR, Drakesmith H (2011) Hepcidin regulation by innate immune and infectious stimuli. Blood 118: 4129–4139 source
• Not checked yetcites [61] Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute‐phase protein. Blood 101: 2461–2463 source

In the paper

“IFNc also induces the expression of iNOS/NOS2 [78], via a mechanism regulated at a transcriptional level by the activation of the signal transducers and activators of transcription (STAT) family of transcription factors (Fig 2).As described above, the NO produced by iNOS/NOS2 regulates the binding affinities of IRP toward target IRE in genes such as transferrin receptor (TfR) and ferritin, inhibit”

What the sources say

• Not checked yetcites [78] Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF‐kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269: 4705–4708 source
• Not checked yetcites [58] Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L (2012) Mechanisms of mammalian iron homeostasis. Biochemistry 51: 5705–5724 source
• Not checked yetcites [81] Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner‐Felmayer G, Wachter H, Hentze MW (1993) Translational regulation via iron‐responsive elements by the nitric oxide/NO‐synthase pathway. EMBO J 12: 3651–3657 source
• Not checked yetcites [82] Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kuhn LC (1993) Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J 12: 3643–3649 source
• Not checked yetcites [111] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16: 3781–3788 source

In the paper

“Moreover, IL-10 and IL-6 also increase heme uptake from circulating hemoglobin-haptoglobin or heme-HPX complexes, via a mechanism involving the induction of the hemoglobin scavenger receptor CD163 and the HPX scavenger receptor CD91 [114,115], respectively (Fig 2).This is coupled to the induction of HO-1 in Mø [116], which extracts Fe from heme and promotes intracellular Fe storage by ferritin (”

What the sources say

• Not checked yetcites [114] Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK (2005) Identification of the receptor scavenging hemopexin‐heme complexes. Blood 106: 2572–2579 source
• Not checked yetcites [115] Schaer DJ, Schaer CA, Buehler PW, Boykins RA, Schoedon G, Alayash AI, Schaffner A (2006) CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107: 373–380 source
• Not checked yetcites [116] Lee TS, Chau LY (2002) Heme oxygenase‐1 mediates the anti‐inflammatory effect of interleukin‐10 in mice. Nat Med 8: 240–246 source

In the paper

“Activated Mø express and release lactoferrin, which scavenges and restricts Fe availability to extracellular pathogens [6,117,118] (Fig 2).Lactoferrin also protects Mø from oxidative stress [117,119] and modulates Mø microbicidal activity, as shown in the context of Staphylococcus aureus infection [120,121].”

What the sources say

• Not checked yetcites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source
• Not checked yetcites [117] Brock JH (2002) The physiology of lactoferrin. Biochem Cell Biol 80: 1–6 source
• Not checked yetcites [118] Kontoghiorghes GJ, Weinberg ED (1995) Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches. Blood Rev 9: 33–45 source
• Not checked yetcites [119] Fischer R, Debbabi H, Dubarry M, Boyaka P, Tome D (2006) Regulation of physiological and pathological Th1 and Th2 responses by lactoferrin. Biochem Cell Biol 84: 303–311 source
• Not checked yetcites [120] Hwang SA, Kruzel ML, Actor JK (2014) Immunomodulatory effects of recombinant lactoferrin during MRSA infection. Int Immunopharmacol 20: 157–163 source
• Not checked yetcites [121] Guillen C, McInnes IB, Vaughan DM, Kommajosyula S, Van Berkel PH, Leung BP, Aguila A, Brock JH (2002) Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin‐transgenic mice. J Immunol 168: 3950–3957 source

In the paper

“For example, heme catabolism by and subsequent intracellular Fe storage by ferritin [54,107] confers host protection against the blood stage of Plasmodium infection while increasing susceptibility to the intracellular bacteria Salmonella [108].”

What the sources say

• Not checked yetcites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source
• Not checked yetcites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source
• Not checked yetcites [108] Cunnington AJ, de Souza JB, Walther M, Riley EM (2012) Malaria impairs resistance to Salmonella through heme‐ and heme oxygenase‐dependent dysfunctional granulocyte mobilization. Nat Med 18: 120–127 source

In the paper

“The general strategy to restrict Fe access to extracellular pathogens consists in the retention of intracellular Fe by Mø leading to hypoferremia (Fig 2).This is achieved essentially by the induction of Fe import and retention mechanisms, coupled to suppression of cellular Fe export (Fig 2).”

In the paper

“Lipocalin (Lcn2/NGAL) is a peptide produced by activated polymorphonuclear (PMN) cells and Mø, which captures Fe-laden bacterial catechole type siderophores, such as enterobactin, derived from Gram-negative bacteria (Fig 2).Lcn2 inhibits the acquisition of siderophore-bound Fe by bacteria, as illustrated for E. coli or Klebsiella spp.[129,130].”

What the sources say

• Not checked yetcites [129] Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432: 917–921 source
• Not checked yetcites [130] Berger T, Togawa A, Duncan GS, Elia AJ, You‐Ten A, Wakeham A, Fong HE, Cheung CC, Mak TW (2006) Lipocalin 2‐deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia‐reperfusion injury. Proc Natl Acad Sci USA 103: 1834–1839 source

In the paper

“Lactoferrin is expressed in many tissues and secretions where its primary function is to bind and restrict Fe delivery to extracellular microbes, a mechanism which accounts for its antimicrobial activity in breast milk [117].”

What the sources say

• Not checked yetcites [117] Brock JH (2002) The physiology of lactoferrin. Biochem Cell Biol 80: 1–6 source

In the paper

“However, once intracellular Fe levels increase in Mø, iNOS/NOS2 transcription is repressed creating a negative feedback loop, which promotes intracellular Fe retention [85,111].”

What the sources say

• Not checked yetcites [85] Weiss G, Wachter H, Fuchs D (1995) Linkage of cell‐mediated immunity to iron metabolism. Immunol Today 16: 495–500 source
• Not checked yetcites [111] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16: 3781–3788 source

In the paper

“Lcn2 delivers bacterial as well as mammalian siderophore-bound Fe [131,132] to the Lcn2 receptor expressed by host cells, suggesting that it modulates Fe trafficking and hence Fe metabolism during infection (Fig 2).”

What the sources say

• Not checked yetcites [131] Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141: 1006–1017 source
• Not checked yetcites [132] Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T et al (2010) Iron traffics in circulation bound to a siderocalin (Ngal)‐catechol complex. Nat Chem Biol 6: 602–609 source

In the paper

“Murine Mø lacking functional Nramp1 have a higher intracellular Fe content, whereas functional Nramp1 decreases intracellular Fe content, conferring protection against intracellular infections [145,148,149], an effect traced back to modulation of FPN expression [150].”

What the sources say

• Not checked yetcites [145] Cellier MF (2012) Nutritional immunity: homology modeling of Nramp metal import. Adv Exp Med Biol 946: 335–351 source
• Not checked yetcites [148] Barton CH, Biggs TE, Baker ST, Bowen H, Atkinson PG (1999) Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens. J Leukoc Biol 66: 757–762 source
• Not checked yetcites [149] Fritsche G, Nairz M, Theurl I, Mair S, Bellmann‐Weiler R, Barton HC, Weiss G (2007) Modulation of macrophage iron transport by Nramp1 (Slc11a1). Immunobiology 212: 751–757 source
• Not checked yetcites [150] Nairz M, Fritsche G, Crouch ML, Barton HC, Fang FC, Weiss G (2009) Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition. Cell Microbiol 11: 1365–1381 source

In the paper

“NRAMP1 increases the production of NO and TNF in infected Mø, whereas IL-10 secretion is reduced, arguing again that modulation of intracellular Fe content regulates Mø antimicrobial effector function [152-155].”

What the sources say

• Not checked yetcites [152] Fritsche G, Dlaska M, Barton H, Theurl I, Garimorth K, Weiss G (2003) Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression. J Immunol 171: 1994–1998 source
• Not checked yetcites [153] Fritsche G, Nairz M, Werner ER, Barton HC, Weiss G (2008) Nramp1‐functionality increases iNOS expression via repression of IL‐10 formation. Eur J Immunol 38: 3060–3067 source
• Not checked yetcites [154] Barton CH, Whitehead SH, Blackwell JM (1995) Nramp transfection transfers Ity/Lsh/Bcg‐related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Mol Med 1: 267–279 source
• Not checked yetcites [155] Mulero V, Searle S, Blackwell JM, Brock JH (2002) Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin‐receptor‐mediated, iron uptake. Biochem J 363: 89–94 source

In the paper

“Overall, this suggests that extracellular hemoglobin acts both as a soluble pattern recognition receptors (PRRs) and as a cytotoxic effector molecule targeting extracellular pathogens [140].”

What the sources say

• Not checked yetcites [140] Lee SK, Ding JL (2013) A perspective on the role of extracellular hemoglobin on the innate immune system. DNA Cell Biol 32: 36–40 source

In the paper

“Extracellular hemoglobin exerts antimicrobial effects, driven by the peroxidase activity of the Fe contained in its prosthetic heme groups [138,139].Furthermore, binding of extracellular hemoglobin to bacterial LPS [140] elicits conformational changes in the tertiary structure of hemoglobin [139,141], which enhance its peroxidase and microbicidal activity [138,139].”

What the sources say

• Not checked yetcites [138] Jiang N, Tan NS, Ho B, Ding JL (2007) Respiratory protein‐generated reactive oxygen species as an antimicrobial strategy. Nat Immunol 8: 1114–1122 source
• Not checked yetcites [139] Du R, Ho B, Ding JL (2010) Rapid reprogramming of haemoglobin structure‐function exposes multiple dual‐antimicrobial potencies. EMBO J 29: 632–642 source
• Not checked yetcites [140] Lee SK, Ding JL (2013) A perspective on the role of extracellular hemoglobin on the innate immune system. DNA Cell Biol 32: 36–40 source
• Not checked yetcites [141] Kaca W, Roth RI, Levin J (1994) Hemoglobin, a newly recognized lipopolysaccharide (LPS)‐binding protein that enhances LPS biological activity. J Biol Chem 269: 25078–25084 source

In the paper

“There is at least one additional mechanism by which NRAMP1 confers resistance to intracellular bacteria such as Salmonella, namely via the induction of Lcn2 expression [156].Of note, Lcn2 can control the proliferation of intracellular bacteria that do not produce siderophores, such as Chlamydia pneumonia [157] (Fig 3).”

What the sources say

• Not checked yetcites [156] Fritsche G, Nairz M, Libby SJ, Fang FC, Weiss G (2012) Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin‐2 expression. J Leukoc Biol 92: 353–359 source
• Not checked yetcites [157] Bellmann‐Weiler R, Schroll A, Engl S, Nairz M, Talasz H, Seifert M, Weiss G (2013) Neutrophil gelatinase‐associated lipocalin and interleukin‐10 regulate intramacrophage Chlamydia pneumoniae replication by modulating intracellular iron homeostasis. Immunobiology 218: 969–978 source

In the paper

“It should be noted, however, that Lcn2 exerts contrasting effects depending on the pathogen and tissue localization, improving or mitigating resistance to infection.For example, Lcn2 aggravates the outcome of Streptococcus pneumoniae infection [134] through a immunomodulatory effect possibly acting via regulation of Fe metabolism or another not yet fully elucidated pathway [135,136].”

What the sources say

• Not checked yetcites [134] Warszawska JM, Gawish R, Sharif O, Sigel S, Doninger B, Lakovits K, Mesteri I, Nairz M, Boon L, Spiel A et al (2013) Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes. J Clin Invest 123: 3363–3372 source
• Not checked yetcites [135] Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 1826: 129–169
• Not checked yetcites [136] Liu Z, Petersen R, Devireddy L (2013) Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections. J Immunol 190: 4692–4706 source

In the paper

“The pathophysiologic relevance of this mechanism is illustrated by the fact that individuals carrying mutations in the FPN gene, which is associated with intracellular Fe retention and secondary siderosis in Africa (also termed Bantu disease), are challenged with an increased incidence of Mycobacteria infection and higher mortality from tuberculosis [162].”

What the sources say

• Not checked yetcites [162] Gordeuk VR, Caleffi A, Corradini E, Ferrara F, Jones RA, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G et al (2003) Iron overload in Africans and African‐Americans and a common mutation in the SCL40A1 (ferroportin 1) gene small star, filled. Blood Cells Mol Dis 31: 299–304 source

In the paper

“Taken together, these observations argue that several mechanisms evolved to regulate host Fe metabolism in a manner that limits the proliferation capacity and virulence of extracellular pathogens.Moreover, leakage of hemoglobin from red blood cells appears to be an ancestral and evolutionary conserved defense strategy that targets extracellular pathogens for heme-driven oxidative cytotoxicity.”

In the paper

“NRAMP1 is a transmembrane transporter expressed in late phagosomes, where it exerts multiple functions including regulation of phagosome acidification, which is, however, exerted mainly by v-ATPase [144] along with pH-dependent shuttling of divalent metals, including Fe, zinc and manganese, across the phagolysosomal membrane [145-147] (Fig 3).”

What the sources say

• Not checked yetcites [144] Sturgill‐Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG et al (1994) Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton‐ATPase. Science 263: 678–681 source
• Not checked yetcites [145] Cellier MF (2012) Nutritional immunity: homology modeling of Nramp metal import. Adv Exp Med Biol 946: 335–351 source
• Not checked yetcites [146] Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, Grinstein S (1998) Host resistance to intracellular infection: mutation of natural resistance‐associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 188: 351–364 source
• Not checked yetcites [147] Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P (2000) Natural resistance to intracellular infections: natural resistance‐associated macrophage protein 1 (Nramp1) functions as a pH‐dependent manganese transporter at the phagosomal membrane. J Exp Med 192: 1237–1248 source

In the paper

“Of note, E. coli can use the mammalian siderophore, 2,5-dihydroxy-benzoic acid (2,5-DHBA) as Fe source [137].Accordingly, Mø respond to bacterial challenge by downregulating 2,5-DHBA synthesis, leading to 2,5-DHBA depletion and enhanced resistance to E. coli infection.”

What the sources say

• Not checked yetcites [137] Liu Z, Reba S, Chen WD, Porwal SK, Boom WH, Petersen RB, Rojas R, Viswanathan R, Devireddy L (2014) Regulation of mammalian siderophore 2,5‐DHBA in the innate immune response to infection. J Exp Med 211: 1197–1213 source

In the paper

“Namely, when produced by iNOS/NOS2 in activated Mø, NO activates Nrf2 and induces the transcription/expression of FPN, which reduces Mø intracellular Fe content and confers resistance to Salmonella infection [73] (Fig 3).Of note, impaired resistance to Salmonella infection in iNos/Nos2-deficient mice can be restored by pharmacologic Fe chelation, arguing that the microbicidal effect of NO acts, at”

What the sources say

• Not checked yetcites [73] Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU et al (2013) Nitric oxide‐mediated regulation of ferroportin‐1 controls macrophage iron homeostasis and immune function in Salmonella infection. J Exp Med 210: 855–873 source

In the paper

“As discussed above, some immune-driven resistance mechanisms can encompass subtle alterations of host Fe metabolism characterized by a systemic”

In the paper

“Intracellular Fe accumulation in Mø represses IFNc receptor signaling, most likely explaining why reducing intracellular Fe content promotes IFNc-driven resistance pathways involving the induction of histocompatibility (MHC) class II, iNOS/NOS2 TNF, IL-6, or IL-12 expression [164][165][166][167].”

What the sources say

• Not checked yetcites [164] Oexle H, Kaser A, Most J, Bellmann‐Weiler R, Werner ER, Werner‐Felmayer G, Weiss G (2003) Pathways for the regulation of interferon‐gamma‐inducible genes by iron in human monocytic cells. J Leukoc Biol 74: 287–294 source
• Not checked yetcites [165] Melillo G, Taylor LS, Brooks A, Musso T, Cox GW, Varesio L (1997) Functional requirement of the hypoxia‐responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine. J Biol Chem 272: 12236–12243 source
• Not checked yetcites [166] Dlaska M, Weiss G (1999) Central role of transcription factor NF‐IL6 for cytokine and iron‐mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162: 6171–6177 source

In the paper

“This is in line with the recent observation that IRP expression and their subsequent regulatory effects on cellular Fe homeostasis in Mø confer resistance to Salmonella infection by restricting Fe availability to the bacterium and by promoting antimicrobial immune effector mechanisms of Mø [168].”

What the sources say

• Not checked yetcites [168] Nairz M, Ferring‐Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015) Iron regulatory proteins mediate host resistance to Salmonella. Cell Host Microbe 18: 254–261 source

In the paper

“Of interest, some intracellular bacteria can counterbalance this host response, as illustrated for Salmonella spp., which promotes the expression of hepcidin in the liver via the induction of estrogen receptor gamma-mediated cascade.Subsequent degradation of FPN favors intracellular Fe accumulation, thereby promoting pathogen growth [163].”

What the sources say

• Not checked yetcites [163] Kim DK, Jeong JH, Lee JM, Kim KS, Park SH, Kim YD, Koh M, Shin M, Jung YS, Kim H et al (2014) Inverse agonist of estrogen‐related receptor gamma controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med 20: 419–424 source

In the paper

“When deposited on the surface of vascular endothelial cells, these become vasoactive and pro-inflammatory [198], presumably contributing to the pathogenesis of systemic infections associated with hemolysis and vasculitis.”

What the sources say

• Not checked yetcites [198] Silva G, Jeney V, Chora A, Larsen R, Balla J, Soares MP (2009) Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells. J Biol Chem 284: 29582–29595 source

In the paper

“This was suggested to contribute to the pathogenesis of severe forms of malaria in mice, without interfering with host pathogen burden [192], thus arguing that NO scavenging by extracellular hemoglobin impairs disease tolerance to Plasmodium infection.”

What the sources say

• Not checked yetcites [192] Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, Intaglietta M, van der Heyde HC (2006) Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med 12: 1417–1422 source

In the paper

“While it is not clear whether this effect is mediated via CO and/or other products of heme catabolism, such as biliverdin and Fe, it is likely that the cytoprotective effect of CO [172] prevents infected Mø from undergoing programmed cell death by necroptosis [173].This cytoprotective effect should support granuloma formation and hence resistance to Mycobacteria [170,171].”

What the sources say

• Not checked yetcites [172] Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192: 1015–1026 source
• Not checked yetcites [173] Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D, Fernandez PL, Souto‐Padron T, De Rosa MJ, Kelliher M, Golenbock D et al (2012) Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 119: 2368–2375 source
• Not checked yetcites [170] Silva‐Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Heme catabolism by heme oxygenase‐1 confers host resistance to Mycobacterium infection. Infect Immun 81: 2536–2545 source
• Not checked yetcites [171] Regev D, Surolia R, Karki S, Zolak J, Montes‐Worboys A, Oliva O, Guroji P, Saini V, Steyn AJ, Agarwal A et al (2012) Heme oxygenase‐1 promotes granuloma development and protects against dissemination of mycobacteria. Lab Invest 92: 1541–1552 source

In the paper

“These often-lethal pathologic conditions can be dissociated from host pathogen burden, suggesting that extracellular hemoglobin impairs disease tolerance to sepsis and malaria.”

In the paper

“Finally, signaling via the IFNc receptor also induces FPN expression while inhibiting extracellular Fe uptake via the transferrin receptor [169] and inducing Lcn2 expression [135] in Mø (Fig 3).”

What the sources say

• Not checked yetcites [169] Nairz M, Fritsche G, Brunner P, Talasz H, Hantke K, Weiss G (2008) Interferon‐gamma limits the availability of iron for intramacrophage Salmonella typhimurium. Eur J Immunol 38: 1923–1936 source
• Not checked yetcites [135] Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 1826: 129–169

In the paper

“The recent finding that Mø necroptosis impairs granuloma formation and compromises resistance to Mycobacteria infection in zebrafish supports this notion [174].”

What the sources say

• Not checked yetcites [174] Roca FJ, Ramakrishnan L (2013) TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153: 521–534 source

In the paper

“It appears that several mechanisms evolved to reduce the intracellular Fe content of Mø infected by intracellular pathogens.This achieves several goals, namely to limit Fe access to intracellular pathogens while modulating Mø polarization and maintaining Mø viability, all of which concur to limit the virulence and eventually clear intracellular pathogens.”

In the paper

“This suggests that mechanisms reducing intracellular Fe availability in Mø have a dual role, limiting microbial access to intracellular Fe while boosting antimicrobial resistance mechanisms in response to cytokines such as IFNc [6].”

What the sources say

• Not checked yetcites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

In the paper

“Presumably, it is this cytotoxic effect that promotes tissue damage and hence compromises disease tolerance to malaria and severe sepsis [103,105,190].”

What the sources say

• Not checked yetcites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source
• Not checked yetcites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source
• Not checked yetcites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

In the paper

“This pro-oxidant effect blunts the activity of redoxsensitive phosphatases controlling JNK activation [213,214], thus inducing programmed cell death in response to TNF [107,213,215].”

What the sources say

• Not checked yetcites [213] Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C et al (2004) Ferritin heavy chain upregulation by NF‐kappaB inhibits TNFalpha‐induced apoptosis by suppressing reactive oxygen species. Cell 119: 529–542 source
• Not checked yetcites [214] Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha‐induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649–661 source
• Not checked yetcites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source
• Not checked yetcites [215] Berberat PO, Katori M, Kaczmarek E, Anselmo D, Lassman C, Ke B, Shen X, Busuttil RW, Yamashita K, Csizmadia E et al (2003) Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J 17: 1724–1726 source

In the paper

“Heme overrides the cytoprotective program set in motion by the transcription factor NF-jB [209], which prevents sustained JNK activation and programmed cell death [210,211].”

What the sources say

• Not checked yetcites [209] Beg AA, Baltimore D (1996) An essential role for NF‐kappaB in preventing TNF‐alpha‐induced cell death. Science 274: 782–784 source
• Not checked yetcites [210] Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A (2001) Inhibition of JNK activation through NF‐kappaB target genes. Nature 414: 313–317 source
• Not checked yetcites [211] Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G (2006) The NF‐kappaB‐mediated control of ROS and JNK signaling. Histol Histopathol 21: 69–80

In the paper

“The pathogenic effects exerted by extracellular hemoglobin and labile heme are countered by adaptive responses that converge at the level of heme catabolism by HO-1 [38,219], providing tissue damage control and disease tolerance to systemic infections [103,105,106] (Fig 4).”

What the sources say

• Not checked yetcites [38] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase‐1. Annu Rev Pharmacol Toxicol 50: 323–354 source
• Not checked yetcites [219] Soares MP, Marguti I, Cunha A, Larsen R (2009) Immunoregulatory effects of HO‐1: how does it work? Curr Opin Pharmacol 9: 482–489 source
• Not checked yetcites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source
• Not checked yetcites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source
• Not checked yetcites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source

In the paper

“When coupled to other mechanisms regulating Fe homeostasis, HO-1 avoids tissue Fe overload and tissue damage while sustaining Fe supply to erythropoiesis to maintain Fe homeostasis during infection [38,54,219,220] (Fig 4).”

What the sources say

• Not checked yetcites [38] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase‐1. Annu Rev Pharmacol Toxicol 50: 323–354 source
• Not checked yetcites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source
• Not checked yetcites [219] Soares MP, Marguti I, Cunha A, Larsen R (2009) Immunoregulatory effects of HO‐1: how does it work? Curr Opin Pharmacol 9: 482–489 source
• Not checked yetcites [220] Soares MP, Bach FH (2009) Heme oxygenase‐1: from biology to therapeutic potential. Trends Mol Med 15: 50–58 source

In the paper

“Heme sensitization to programmed cell death is partially suppressed by pharmacologic inhibition of caspases [106,107], indicating that heme sensitizes cells to undergo apoptosis [216].”

What the sources say

• Not checked yetcites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source
• Not checked yetcites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source
• Not checked yetcites [216] Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817–829 source

In the paper

“The pathogenic effect of labile heme can be dissociated from the host's pathogen burden [103,105,190], suggesting that labile heme impairs disease tolerance to these systemic infections.”

What the sources say

• Not checked yetcites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source
• Not checked yetcites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source
• Not checked yetcites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

In the paper

“This protective effect is not associated with modulation of host pathogen load, revealing that sickle hemoglobin mutations confer disease tolerance to malaria [103,104].”

What the sources say

• Not checked yetcites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source
• Not checked yetcites [104] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 86: 1097–1111 source

In the paper

“Moreover, lactoferrin acts synergistically with antibiotics against Staphylococci infections and can be used to control bovine mastitis [234].”

What the sources say

• Not checked yetcites [234] Diarra MS, Petitclerc D, Lacasse P (2002) Effect of lactoferrin in combination with penicillin on the morphology and the physiology of Staphylococcus aureus isolated from bovine mastitis. J Dairy Sci 85: 1141–1149 source

In the paper

“Namely, sickle hemoglobin mutations induce the generation of labile heme, which triggers the activation of the transcription factor Nrf2 and the expression of 104].”

What the sources say

• Not checked yetcites [104] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 86: 1097–1111 source

In the paper

“Systemic Fe chelation by desferrioxamine can improve the clinical course of malaria, without, however, providing an overt survival benefit [236].”

What the sources say

• Not checked yetcites [236] Gordeuk V, Thuma P, Brittenham G, McLaren C, Parry D, Backenstose A, Biemba G, Msiska R, Holmes L, McKinley E et al (1992) Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 327: 1473–1477 source

In the paper

“However, the Fe chelator desferasirox, which cannot be used by molds to acquire Fe, improves survival of infected mice, limiting Fe availability to the pathogen while enhancing host resistance mechanisms [238].”

What the sources say

• Not checked yetcites [238] Ibrahim AS, Gebermariam T, Fu Y, Lin L, Husseiny MI, French SW, Schwartz J, Skory CD, Edwards JE Jr, Spellberg BJ (2007) The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest 117: 2649–2657 source

In the paper

“In addition, CO modulates signaling by PRRs, as illustrated for TLR4, inhibiting TNF while increasing IL-10 secretion by activated Mø [225].”

What the sources say

• Not checked yetcites [225] Otterbein LE, Bach FH, Alam J, Soares MP, Tao HL, Wysk M, Davis R, Flavell R, Choi AMK (2000) Carbon monoxide mediates anti‐inflammatory effects via the mitogen activated protein kinase pathway. Nat Med 6: 422–428 source

In the paper

“The protective effects of FTH do not interfere with host pathogen burden, illustrating further how regulation of host Fe metabolism confers disease tolerance to infection [103,106,190].”

What the sources say

• Not checked yetcites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source
• Not checked yetcites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source
• Not checked yetcites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

In the paper

“The proof of principle for this approach was provided for Vibrio vulnificus infection in mice [96].”

What the sources say

• Not checked yetcites [96] Arezes J, Jung G, Gabayan V, Valore E, Ruchala P, Gulig PA, Ganz T, Nemeth E, Bulut Y (2015) Hepcidin‐induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17: 47–57 source

In the paper

“Tf transports and provides Fe to the erythropoietic compartment via TfR, where it is used for heme synthesis (bottom right).”

In the paper

“Immune responses to extracellular pathogens encompass the production of cytokines, for example, IL-1, IL-6, and IL-22, which induce the transcription of the hepcidin (HAMP) gene in hepatocytes.”

In the paper

“Oxidized extracellular hemoglobin can also release heme, which acts as a pro-inflammatory agonist in endothelial cells and Mø via TLR4, or via GPCRs in PMN cells.”

In the paper

“For example, extracellular hemoglobin can scavenge NO, promoting vasoconstriction and eventually affecting microvascular circulation (top).”

In the paper

“This relationship is complex and pathogen class-specific strategies evolved to control Fe and heme availability to intracellular versus extracellular pathogens.”

In the paper

“Finally, CO is a potent cytoprotective molecule that prevents tissue damage and as such can enforce disease tolerance to infection.”

In the paper

“IFNcR signaling also inhibits Fe extracellular uptake via TfR.”

In the paper

“Labile heme sensitizes parenchyma cells to undergo programmed cell death in response to TNF, leading to tissue damage and compromising disease tolerance (right).”

In the paper

“Circulating hepcidin targets systemically the Fe export protein FPN for degradation, which inhibits Fe cellular retention in many cell types, including Mø, which are pivotal to the maintenance of Fe homeostasis.”

In the paper

“In addition, Mø can engulf damaged RBC and prevent hemoglobin release or (H) scavenge extracellular hemoglobin/haptoglobin via the scavenger receptor CD163 as well as (I) heme/HPX complexes via the scavenger receptor CD91.”

In the paper

“Lcn2 neutralizes the action of bacterial siderophores.”

In the paper

“Pathogen virulence often emerges via natural selection of genes that favor Fe and/or heme uptake by microbes, suggesting that targeting such mechanisms may be of therapeutic value to combat infectious diseases.”

In the paper

“These include ferritin, which stores intracellular Fe and FPN, which delivers Fe to Tf and supports erythropoiesis.”

In the paper

“Heme synthesis occurs via eight successive enzymatic reactions that take place back and forward in the mitochondria (brown) and the cytosol (blue).”

In the paper

“The Fe required to sustain hemoglobin synthesis is made available by hemophagocytic Mø as these clear senescent RBC by erythrophagocytosis (top right)[49].”

What the sources say

• Not checked yetcites [49] Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125: 2893–2897 source

In the paper

“Moreover, HO-1 enzymatic activity generates CO, which promotes the secretion of IL-10 in activated Mø, impacting on MHC class II/TCR-driven activation of T H cells and thereby contributing to tissue damage control and eventually to disease tolerance (middle).”

In the paper

“The heme contained in hemoglobin is transported by heme-responsive gene-1 (HRG1) into the cytoplasm where Fe is extracted by hemeoxygnease-1 (HO-1), exported via ferroportin (FPN), and delivered to traferrin (Tf) in plasma.”

In the paper

“Uptake of heme/HPX, damaged RBC, or hemoglobin/haptoglobin by Mø is coupled to heme transport from phagolysomes to the cytoplasm, by the heme transporter HRG1, and to heme catabolism by HO-1.”

In the paper

“This prevents anemia and tissue hypoxia, an effect likely to promote disease tolerance.”

In the paper

“Cellular Fe retention by Mø can lead to the development of anemia of inflammation, which triggers the production of several hormones, such as Epo, Erfe, GDF15, PDGF-BB, or the activation of the HIF family of transcription factors, which reduce hepcidin expression.”

In the paper

“Lactoferrin binds Fe and limits its availability to bacteria.”

In the paper

“Surplus cytoplasmic Fe in Mø is incorporated and stored within ferritin.”