The role of iron in the immune response to bacterial infection

Abstract

My laboratory has been interested for some time in the influence of iron, a nutrient that is essential for both microbial pathogens and their mammalian hosts, on the course of infectious disease. Our studies indicate that alterations in the expression of host molecules that sequester or transport iron can have direct effects on pathogen growth and can also have an impact on the ability to mount normal immune responses. We have elucidated the mechanistic basis for some of these observations, and have started to apply our findings in strategies to control abnormalities of inflammation and iron metabolism. I will review here what we have learned about the interactions between iron and immunity and discuss the implications of the information that we have acquired.

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References

  1. 1.

    Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001;131:568S–80S.

    PubMed  CAS  Google Scholar 

  2. 2.

    Andrews NC. Forging a field: the golden age of iron biology. Blood. 2008;112:219–30.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Hentze MW, Muckenthaler MU, Galy B, et al. Two to tango: regulation of mammalian iron metabolism. Cell. 2010;142:24–38.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Biggs TE, Baker ST, Botham MS, et al. Nramp1 modulates iron homeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de-acidification of intracellular vesicles. Eur J Immunol. 2001;31:2060–70.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Soe-Lin S, Sheftel AD, Wasyluk B, et al. Nramp1 equips macrophages for efficient iron recycling. Exp Hematol. 2008;36:929–37.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Soe-Lin S, Apte SS, Andriopoulos B Jr, et al. Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci USA. 2009;106:5960–5.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399–408.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalin iron sensing. J Biol Chem. 2006;281:28494–8.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Schmidt PJ, Toran PT, Giannetti AM, et al. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7:205–14.

    PubMed  Article  Google Scholar 

  10. 10.

    Gao J, Chen J, Kramer M, et al. Interaction of the hereditary hemochromatosis protein, HFE, with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 2009;9:217–27.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Andriopoulos B, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482–7.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Meynard D, Kautz L, Darnaud V, et al. Lack of BMP6 induces massive iron overload. Nat Genet. 2009;41:478–81.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:13.1–4. (epub ahead of print).

    Article  Google Scholar 

  14. 14.

    Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–3.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569–78.

    PubMed  Article  Google Scholar 

  16. 16.

    De Domenico I, Lo E, Ward DM, et al. Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2. Proc Natl Acad Sci USA. 2009;106:3800–5.

    PubMed  Article  Google Scholar 

  17. 17.

    Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6.

    PubMed  CAS  Google Scholar 

  18. 18.

    Lee P, Peng H, Gelbart T, Beutler E. The IL-6 and LPS-induced transcription of hepcidin in Hfe- TfR2- and β2-microglobulin-deficient mice. Proc Natl Acad Sci USA. 2004;101:9263–5.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Lee P, Peng H, Gelbart T, et al. Regulation of hepcidin transcription by IL-1 and IL-6. Proc Natl Acad Sci USA. 2005;102:1906–10.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Wang L, Cherayil BJ. Ironing out the wrinkles in host defense: interactions between iron homeostasis and innate immunity. J Innate Immun. 2009;1:455–64.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Forbes JR, Gros P. Divalent metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol. 2001;9:397–403.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Cellier MF, Courville P, Campion C. Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect. 2007;9:1662–70.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Moller M, Hoal EG. Current findings, challenges and novel approaches to human genetic susceptibility to tuberculosis. Tuberculosis (Edinb). 2010;90:71–83.

    Article  CAS  Google Scholar 

  25. 25.

    Chlosta S, Fishman DS, Harrington L, et al. The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infect Immun. 2006;74:3065–7.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Olakanmi O, Schlesinger LS, Britigan BE. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J Leukoc Biol. 2007;81:195–204.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Nairz M, Theurl I, Ludwiczek S, et al. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol. 2007;9:2126–40.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Paradkar PN, De Domenico I, Durchfort N, et al. Iron depletion limits intracellular bacterial growth in macrophages. Blood. 2008;112:866–74.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Nairz M, Fritsche G, Brunner P, et al. Interferon γ limits the availability of iron for intra-macrophage Salmonella typhimurium. Eur J Immunol. 2008;38:1923–36.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Peyssonaux C, Zinkernagel AS, Datta V, et al. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood. 2006;107:3727–32.

    Article  Google Scholar 

  31. 31.

    Nguyen NB, Callaghan KD, Ghio AJ, et al. Hepcidin expression and iron transport in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2006;291:L417–25.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Theurl I, Theurl M, Seifert M, et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood. 2008;111:2392–9.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol. 2004;2:946–53.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Doherty CP. Host-pathogen interactions: the role of iron. J Nutr. 2007;137:1341–4.

    PubMed  CAS  Google Scholar 

  35. 35.

    Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010;139:393–408.

    PubMed  Article  Google Scholar 

  36. 36.

    Zhou XY, Tomatsu S, Fleming RE, et al. Hfe gene knock-out produces a mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA. 1998;95:2492–7.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Wang L, Johnson EE, Shi HN, et al. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008;181:2723–31.

    PubMed  CAS  Google Scholar 

  38. 38.

    Gomes-Pereira S, Rodrigues PN, Appelberg R, et al. Increased susceptibility to Mycobacterium avium in hemochromatosis protein Hfe-deficient mice. Infect Immun. 2008;76:4713–9.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Johnson EE, Sandgren A, Cherayil BJ, et al. Role of ferroportin in macrophage-mediated immunity. Infect Immun. 2010;78:5099–106.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Wang L, Harrington L, Trebicka E, et al. Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J Clin Invest. 2009;119:3322–8.

    PubMed  CAS  Google Scholar 

  41. 41.

    Sheedy FJ, O’Neill LA. The Troll in Toll: Mal and TRAM as bridges for TLR2 and TLR4 signaling. J Leukoc Biol. 2007;82:196–203.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Kagan JC, Su T, Horng T, et al. TRAM couples endocytosis of TLR4 to the induction of interferon-beta. Nat Immunol. 2008;9:361–8.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Nairz M, Theurl I, Schroll A, et al. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2. Blood. 2009;114:3642–51.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Levy JE, Montross LK, Cohen DE, et al. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood. 1999;94:9–11.

    PubMed  CAS  Google Scholar 

  46. 46.

    Bahram S, Gilfillan S, Kuhn LC, et al. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA. 1999;96:13312–7.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    De Domenico I, Zhang TY, Branch LW, et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010;120:2395–405.

    PubMed  Article  Google Scholar 

  48. 48.

    Bullen JJ, Spalding PB, Ward CG, et al. Hemochromatosis, iron and septicemia caused by Vibrio vulnificus. Arch Intern Med. 1991;151:1606–9.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Bergmann TK, Vinding K, Hey H. Multiple hepatic abscesses due to Yersinia enterocolitica infection secondary to primary hemochromatosis. Scand J Gastroenterol. 2001;36:891–5.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Wright AC, Simpson LM, Oliver JD. Role of iron in the pathogenesis of Vibrio vulnificus infections. Infect Immun. 1981;34:503–7.

    PubMed  CAS  Google Scholar 

  51. 51.

    Gordeuk VR, Ballou S, Lozanski G, et al. Decreased concentrations of TNFα in supernatants of monocytes from homozygotes for hereditary hemochromatosis. Blood. 1992;79:1855–60.

    PubMed  CAS  Google Scholar 

  52. 52.

    Gordeuk VR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SLC40A1 (ferroportin 1) gene. Blood Cells Mol Dis. 2003;31:299–304.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Beutler E, Barton JC, Felitti VJ, et al. Ferroportin 1 (SLC40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis. 2003;31:305–9.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    McNamara L, Gordeuk VR, MacPhail AP. Ferroportin (Q248H) mutations in African families with dietary iron overload. J Gastroenterol Hepatol. 2005;20:1855–8.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Boelaert JR, Vandecasteele SJ, Appelberg R, et al. The effect of the host’s iron status on tuberculosis. J Infect Dis. 2007;195:1745–53.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Gomolion F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol. 2009;15:4659–65.

    Article  Google Scholar 

  57. 57.

    Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia in patients with IBD. Nat Rev Gastroenterol Hepatol. 2010;7:599–610.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Ganz T, Nemeth E. Iron sequestration and anemia of inflammation. Semin Hematol. 2009;46:387–93.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu Rev Nutr. 2010;30:105–22.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Semrin G, Fishman DS, Bousvaros A, et al. Impaired intestinal iron absorption in Crohn’s disease correlates with disease activity and markers of inflammation. Inflamm Bowel Dis. 2006;12:1101–6.

    PubMed  Article  Google Scholar 

  61. 61.

    Cherayil BJ. Cross-talk between iron homeostasis and intestinal inflammation. Gut Microbes. 2010;1:65–9.

    PubMed  Article  Google Scholar 

  62. 62.

    Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933–9.

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2008;4:33–41.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Berg DJ, Zhang J, Weinstock JV, et al. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology. 2002;123:1527–42.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Legrand D, Mazurier J. A critical review of the roles of host lactoferrin in immunity. Biometals. 2010;23:365–76.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Ward PP, Mendoza-Meneses M, Park PW, et al. Stimulus-dependent impairment of neutrophil oxidative burst response in lactoferrin-deficient mice. Am J Pathol. 2008;172:1019–29.

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Clifton MC, Corrent C, Strong RK. Siderocalins: siderophore-binding proteins of the innate immune system. Biometals. 2009;22:557–64.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Goetz DH, Holmes MA, Borregaard N, et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002;10:1033–43.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen contol. Microbiol Mol Biol Rev. 2007;71:413–51.

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 2004;432:917–21.

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Berger T, Togawa A, Duncan GS, et al. Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2006;103:1834–9.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Chan YR, Liu JS, Pociask DA, et al. Lipocalin 2 is required for pulmonary host defense against Klebsiella infection. J Immunol. 2009;182:4947–56.

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Fischbach MA, Lin H, Liu DR, et al. How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol. 2006;2:132–8.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Fischbach MA, Lin H, Zhou L, et al. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci USA. 2006;103:16502–7.

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Raffatellu M, George MD, Akiyama Y, et al. Lipocalin 2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe. 2009;5:476–86.

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Holmes MA, Paulsene W, Jide X, et al. Siderocalin (Lcn2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure. 2005;13:29–41.

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Saiga H, Nishimura J, Kuwata H, et al. Lipocalin 2-dependent inhibition of mycobacterial growth in alveolar epithelium. J Immunol. 2008;181:8521–7.

    PubMed  CAS  Google Scholar 

  78. 78.

    Johnson EE, Srikanth CV, Sandgren A, et al. Siderocalin inhibits the intracellular replication of Mycobacterium tuberculosis in macrophages. FEMS Immunol Med Microbiol. 2010;58:138–45.

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Martineau AR, Newton SM, Wilkinson KA, et al. Neutrophil-mediated innate immune resistance to mycbacteria. J Clin Invest. 2007;117:1988–94.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Landro L, Damas JK, Flo TH, et al. Decreased serum lipocalin 2 levels in human immunodeficiency virus-infected patients: increase during highly active anti-retroviral therapy. Clin Exp Immunol. 2008;152:57–63.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Devireddy LR, Hart DO, Goetz DH, et al. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 2010;141:1006–17.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Bao G, Clifton M, Hoette TM, et al. Iron traffics in circulation bound to a siderocalin (NGAL)-catechol complex. Nat Chem Biol. 2010;6:602–9.

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Philpott C. Bioinorganic chemistry: getting a grip on iron. Nat Chem Biol. 2010;6:568–70.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Yang J, Goetz D, Li JY, et al. An iron delivery pathway mediated by lipocalin. Mol Cell. 2002;10:1045–56.

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Kaplan J. Mechanisms of cellular iron acquisition: another iron in the fire. Cell. 2002;111:603–6.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Devireddy LR, Gazin C, Zhu X, et al. A cell surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005;123:1293–305.

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Richardson DR. 24p3 and its receptor: dawn of a new iron age? Cell. 2005;123:1175–7.

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Breuer W, Shvartsman M. Cabantchik ZI: Intracellular labile iron. Int J Biochem Cell Biol. 2008;40:350–4.

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Kell DB. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular, other progressive inflammatory, degenerative diseases. BMC Med Genomics. 2009;2:2.

    PubMed  Article  Google Scholar 

  90. 90.

    Kell DB. Towards a unifying systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol. 2010;84:825–89.

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Baker M, Wilson D, Sabeti PC, et al. Host genetic factors involved in iron regulation may influence susceptibility to Mycobacterium tuberculosis: a pilot study. Abstract presented at the Fourth Annual New England TB Symposium, July 2010.

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Acknowledgments

Work in the author’s laboratory is supported by grants from the National Institutes of Health (R56AI089700), the Broad Medical Research Program (IBD-0253) and the Crohn’s and Colitis Foundation of America (1754).

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Correspondence to Bobby J. Cherayil.

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Cherayil, B.J. The role of iron in the immune response to bacterial infection. Immunol Res 50, 1–9 (2011). https://doi.org/10.1007/s12026-010-8199-1

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Keywords

  • Iron metabolism
  • Infection
  • Inflammation
  • Macrophage
  • Siderophore