Ironing out the wrinkles in host defense: Interactions between iron homeostasis and innate immunity

Journal of Innate Immunity

Volumn 1, Issue 5, 2009, Pages 455-464

  Wang, Lijian ^a,c   Cherayil, Bobby J ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Inflammation; Iron homeostasis; Macrophage

Indexed keywords

HEPCIDIN; HYPOXIA INDUCIBLE FACTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IRON; IRON BINDING PROTEIN;

DEFENSE MECHANISM; HOMEOSTASIS; HOST RESISTANCE; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; IRON METABOLISM; IRON TRANSPORT; MACROPHAGE; MAMMAL; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INTERACTION; REVIEW;

ANIMALS; BACTERIA; BACTERIAL INFECTIONS; HOMEOSTASIS; HUMANS; IMMUNITY, INNATE; IRON;

EID: 70449379573     PISSN: 1662811X     EISSN: 16628128     Source Type: Journal    
DOI: 10.1159/000210016     Document Type: Review

References (88)

1. Rodriguez GM: Control of iron metabolism in Mycobacterium tuberculosis. Trends Microbiol 2006;14:320-327.
2. Miethke M, Marahiel MA: Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 2007;71:413-451. (Pubitemid 47429279)
3. Huynh C, Andrews NW: Iron acquisition within host cells and the pathogenicity of Leishmania . Cell Microbiol 2008;10:293-300.
4. Sutak R, Lesuisse E, Tachezy J, Richardson DR: Crusade for iron: iron uptake in unicellular eukaryotes and its significance for virulence. Trends Microbiol 2008;16:261-268.
5. Andrews NC, Schmidt PJ: Iron homeostasis. Annu Rev Physiol 2007;69:69-85.
6. De Domenico I, McVey Ward D, Kaplan J: Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol 2008;9:72-81.
7. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-2093. (Pubitemid 40007660)
8. Nemeth E: Iron regulation and erythropoiesis. Curr Opin Hematol 2008;15:169-175.
9. Muckenthaler MU: Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab 2008;8:1-3.
10. Rouault TA: The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2006;2:406-414. (Pubitemid 44114917)
11. 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.
12. Moyo VM, Gangaidzo IT, Gordeuk VR, Kiire CF, Macphail AP: Tuberculosis and iron overload in Africa: a review. Cent Afr J Med 1997;43:334-339.
13. Magnus SA, Hambleton IR, Moosdeen F, Serjeant GR: Recurrent infections in homozygous sickle cell disease. Arch Dis Child 1999;80:537-541. (Pubitemid 29264367)
14. Wanachiwanawin W: Infections in Eβ thalassemia: J Pediatr Hematol Oncol 2000;22:581-587.
15. Gangaidzo IT, Moyo VM, Mvundura E, Aggrey G, Murphree NL, Khumalo H, Saungweme T, Kasvosve I, Gomo ZA, Rouault T, Boelaert JR, Gordeuk VR: Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis 2001;184:936-939. (Pubitemid 32881103)
16. Murray MJ, Murray AB, Murray MB, Murray CJ: The adverse effect of iron repletion on the course of certain infections. Br Med J 1978;2:1113-1115.
17. Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Bäck R, Kortok M, Chemtai AK, Marsh K, Williams TN: Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis 2004;190:439-447. (Pubitemid 38982079)
18. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM: Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community- based, randomised, placebo-controlled trial. Lancet 2006;367:133-143. (Pubitemid 43077129)
19. Schaible UE, Kaufmann SH: Iron and microbial infection. Nat Rev Microbiol 2004;2:946-953.
20. Doherty CP: Host-pathogen interactions: the role of iron. J Nutr 2007;137:1341-1344.
21. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY: Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-539.
22. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY: Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007;117:1933-1939. (Pubitemid 47036327)
23. De Domenico I, Ward DM, Kaplan J: Hepcidin regulation: ironing out the details. J Clin Invest 2007;117:1755-1758. (Pubitemid 47036308)
24. Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY: Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 2008;111:5195-5204.
25. Ganz T: Hepcidin - a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol 2006;306:183-198.
26. Motley ST, Morrow BJ, Liu X, Dodge IL, Vitiello A, Ward CK, Shaw KJ: Simultaneous analysis of host and pathogen interactions during an in vivo infection reveals local induction of host acute phase response proteins, a novel bacterial stress response, and evidence of a host-imposed metal ion limited environment. Cell Microbiol 2004;6:849-865. (Pubitemid 39162627)
27. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT: Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 2008;4:33-41. (Pubitemid 350273653)
28. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S: Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knock-out mice. Proc Natl Acad Sci USA 2001;98:8780-8785. (Pubitemid 32678104)
29. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC: Hepcidin anti-microbial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007;109:4038-4044. (Pubitemid 46641759)
30. Zohn IE, De Domenico I, Pollock A, Ward DM, Goodman JF, Liang X, Sanchez AJ, Niswander L, Kaplan J: The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 2007;109:4174-4180. (Pubitemid 46743381)
31. Johnson EE, Wessling-Resnick M: Flatiron mice and ferroportin disease. Nutr Rev 2007;65:341-345.
32. Marquis JF, Gros P: Genetic analysis of resistance to infections in mice: A/J meets C57BL6/J. Curr Top Microbiol Immunol 2008;321:27-57.
33. Fortier A, Min-Oo G, Forbes J, Lam-Yuk-Tseung S, Gros P: Single gene effects in mouse models of host: pathogen interactions. J Leukoc Biol 2005;77:868-877. (Pubitemid 40770837)
34. Cellier MF, Courville P, Campion C: Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 2007;9:1662-1670. (Pubitemid 350225742)
35. Blackwell JM, Goswami T, Evans CA, Sibthorpe D, Papo N, White JK, Searle S, Miller EN, Peacock CS, Mohammed H, Ibrahim M: Slc11a1 (formerly Nramp1) and disease resistance. Cell Microbiol 2001;3:773-784. (Pubitemid 33133474)
36. Abe T, Iinuma Y, Ando M, Yokoyama T, Yamamoto T, Nakashima K, Takagi N, Baba H, Hasegawa Y, Shimokata K: Nramp1 polymorphisms, susceptibility and clinical features of tuberculosis. J Infect 2003;46:215-220. (Pubitemid 36758179)
37. Li HT, Zhang TT, Zhou YQ, Huang QH, Huang J: Slc11a1 (formerly Nramp1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int J Tuberc Lung Dis 2006;10:3-12.
38. Chlosta S, Fishman DS, Harrington L, Johnson EE, Knutson MD, Wessling-Resnick M, Cherayil BJ: The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica . Infect Immun 2006;74:3065-3067.
39. 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.
40. Gomes-Pereira S, Rodrigues PN, Appelberg R, Gomes MS: Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient mice. Infect Immun 2008;76:4713-4719.
41. Paradkar PN, De Domenico I, Durchfort N, Zohn I, Kaplan J, Ward DM: Iron depletion limits intracellular bacterial growth in macrophages. Blood 2008;112:866-874.
42. Nairz M, Theurl I, Ludwiczek S, Theurl M, Mair SM, Fritsche G, Weiss G: The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol 2007;9:2126-2140. (Pubitemid 47250286)
43. Van Zandt KE, Sow FB, Florence WC, Zwilling BS, Satoskar AR, Schlesinger LS, Lafuse WP: The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial- containing phagosome. J Leukoc Biol 2008;84:689-700.
44. Nairz M, Fritsche G, Brunner P, Talasz H, Hantke K, Weiss G: Interferon γ limits the availability of iron for intra-macrophage Salmonella typhimurium. Eur J Immunol 2008;38:1923-1936.
45. Ward PP, Paz E, Conneely OM: Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005;62:2540-2548. (Pubitemid 41721229)
46. Legrand D, Elass E, Carpentier M, Mazurier J: Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci 2005;62:2549-2559. (Pubitemid 41722207)
47. Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM: Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol 2003;23:178-185. (Pubitemid 36008511)
48. Ward PP, Mendoza-Meneses M, Park PW, Conneely OM: Stimulus-dependent impairment of the neutrophil oxidative burst response in lactoferrin-deficient mice. Am J Pathol 2008;172:1019-1029.
49. Fischbach MA, Lin H, Liu DR, Walsh CT: How pathogenic bacteria evade mammalian sabotage in the battle for iron. Nat Chem Biol 2006;2:132-138. (Pubitemid 44323863)
50. Hantke K: Iron and metal regulation in bacteria. Curr Opin Microbiol 2001;4:172-177.
51. Jacobi CA, Gregor S, Rakin A, Heesemann J: Expression analysis of the yersiniabactin receptor fyuA and the heme receptor hemR of Yersinia enterocolitica in vitro and in vivo using the reporter genes for green fluorescent protein and luciferase. Infect Immun 2001;69:7772-7782.
52. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK: The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 2002;10:1033-1043. (Pubitemid 36001971)
53. Holmes MA, Paulsene W, Jide X, Ratledge C, Strong RK: Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure 2005;13:29-41. (Pubitemid 40092472)
54. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A: Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004;432:917-921. (Pubitemid 40037155)
55. Nelson AL, Barasch JM, Bunte RM, Weiser JN: Bacterial colonization of nasal mucosa induces expression of siderocalin, an iron-sequestering component of innate immunity. Cell Microbiol 2005;7:1404-1417.
56. Draper DW, Bethea HN, He YW: Toll-like receptor 2-dependent and -independent activation of macrophages by group B streptococci. Immunol Lett 2006;102:202-214. (Pubitemid 43053089)
57. Rodríguez N, Mages J, Dietrich H, Wantia N, Wagner H, Lang R, Miethke T: MyD88-dependent changes in the pulmonary transcriptome after infection with Chlamydia pneumoniae . Physiol Genomics 2007;30:134-145.
58. Berger T, Togawa A, Duncan GS, Elia AJ, You-Ten A, Wakeham A, Fong HE, Cheung CC, Mak TW: Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA 2006;103:1834-1839.
59. Saiga H, Nishimura J, Kuwata H, Okuyama M, Matsumoto S, Sato S, Matsumoto M, Akira S, Yoshikai Y, Honda K, Yamamoto M, Takeda K: Lipocalin 2-dependent inhibition of mycobacterial growth in alveolar epithelium. J Immunol 2008;181:8521-8527.
60. Martineau AR, Newton SM, Wilkinson KA, Kampmann B, Hall BM, Nawroly N, Packe GE, Davidson RN, Griffiths CJ, Wilkinson RJ: Neutrophil-mediated innate immune resistance to mycobacteria. J Clin Invest 2007;117:1988-1994. (Pubitemid 47036333)
61. Fischbach MA, Lin H, Zhou L, Yu Y, Abergel RJ, Liu DR, Raymond KN, Wanner BL, Strong RK, Walsh CT, Aderem A, Smith KD: The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci USA 2006;103:16502-16507. (Pubitemid 44715225)
62. Devireddy LR, Teodoro JG, Richard FA, Green MR: Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 2001;293:829-834.
63. Devireddy LR, Gazin C, Zhu X, Green MR: A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005;123:1293-1305. (Pubitemid 41821786)
64. Pietrangelo A: Hereditary hemochromatosis. Annu Rev Nutr 2006;26:251-270.
65. Gardenghi S, Marongiu MF, Ramos P, Guy E, Breda L, Chadburn A, Liu Y, Amariglio N, Rechavi G, Rachmilewitz EA, Breuer W, Cabantchik ZI, Wrighting DM, Andrews NC, de Sousa M, Giardina PJ, Grady RW, Rivella S: Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 2007;109:5027-5035. (Pubitemid 46827803)
66. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007;13:1096-1101. (Pubitemid 47517510)
67. Templeton DM, Liu Y: Genetic regulation of cell function in response to iron overload or chelation. Biochim Biophys Acta 2003;1619:113-124.
68. Hayden MS, Ghosh S: Signaling to NF-κB. Genes Dev 2004;18:2195-2224.
69. Ghosh S, Hayden MS: New regulators of NF-κB in inflammation. Nat Rev Immunol 2008;8:837-848.
70. Bubici C, Papa S, Dean K, Franzoso G: Mutual cross-talk between reactive oxygen species and NF-κB: molecular basis and biological significance. Oncogene 2006;25:6731-6748. (Pubitemid 44657849)
71. She H, Xiong S, Lin M, Zandi E, Giulivi C, Tsukamoto H: Iron activates NF-κB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol 2002; 83:G719-G726. (Pubitemid 34920362)
72. Chen L, Xiong S, She H, Lin SW, Wang J, Tsukamoto H: Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IκB kinase in hepatic macrophages. J Biol Chem 2007;282:5582-5588. (Pubitemid 47093779)
73. Xiong S, She H, Takeuchi H, Han B, Engelhardt JF, Barton CH, Zandi E, Giulivi C, Tsukamoto H: Signaling role of intracellular iron in NF-κB activation. J Biol Chem 2003;278:17646-17654. (Pubitemid 36799366)
74. Stocker R, Perrella MA: Heme oxygenase-1: a novel drug target for atherosclerotic diseases? Circulation 2006;114:2178-2189.
75. Ryter SW, Choi AM: Cytoprotective and anti-inflammatory actions of carbon monoxide in organ injury and sepsis models. Novartis Found Symp 2007;280:165-181.
76. Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui TY, Bach FH: Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol 2004;172:3553-3563. (Pubitemid 38337936)
77. Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, Filipe J, Anrather J, Soares MP: Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-κB RelA phosphorylation at serine 276. J Immunol 2007;179:7840-7851.
78. Kaelin WG Jr, Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008;30:393-402.
79. Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS: HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003;112:645-657. (Pubitemid 36331777)
80. Peyssonnaux C, Datta V, Cramer T, Doedens A, Theodorakis EA, Gallo RL, Hurtado-Ziola N, Nizet V, Johnson RS: HIF-1α expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005;115:1806-1815. (Pubitemid 40979719)
81. Zinkernagel AS, Johnson RS, Nizet V: Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 2007;85:1339-1346.
82. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M: NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008;453:807-811. (Pubitemid 351793778)
83. Hartmann H, Eltzschig HK, Wurz H, Hantke K, Rakin A, Yazdi AS, Matteoli G, Bohn E, Autenrieth IB, Karhausen J, Neumann D, Colgan SP, Kempf VA: Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 2008;134:756-767. (Pubitemid 351312723)
84. Choi EY, Kim EC, Oh HM, Kim S, Lee HJ, Cho EY, Yoon KH, Kim EA, Han WC, Choi SC, Hwang JY, Park C, Oh BS, Kim Y, Kimm KC, Park KI, Chung HT, Jun CD: Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways. J Immunol 2004;172:7069-7077. (Pubitemid 38669149)
85. Markel TA, Crisostomo PR, Wang M, Herring CM, Lahm T, Meldrum KK, Lillemoe KD, Rescorla FJ, Meldrum DR: Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling. Am J Physiol Gastrointest Liver Physiol 2007;292:G958-G963. (Pubitemid 46557767)
86. Choi EY, Park ZY, Choi EJ, Oh HM, Lee S, Choi SC, Lee KM, Im SH, Chun JS, Jun CD: Transcriptional regulation of IL-8 by iron chelator in human epithelial cells is independent from NF-κB but involves ERK1/2- and p38 kinase-dependent activation of AP-1. J Cell Biochem 2007;102:1442-1457. (Pubitemid 350223947)
87. Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ: Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol 2008;181:2723-2731.
88. Bullen JJ, Spalding PB, Ward CG, Gutteridge JM: Hemochromatosis, iron and septicemia caused by Vibrio vulnificus. Arch Intern Med 1991;151:1606-1609.