1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Macrophages and Iron Metabolism

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Buy this Microbiology Spectrum Article
Price Non-Member $15.00
  • Author: Tomas Ganz1
  • Editor: Siamon Gordon2
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 2: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0037-2016
  • Received 30 May 2016 Accepted 06 September 2016 Published 21 October 2016
  • Tomas Ganz, TGanz@mednet.ucla.edu
image of Macrophages and Iron Metabolism
    Preview this microbiology spectrum article:
    Zoom in
    Zoomout

    Macrophages and Iron Metabolism, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/4/5/MCHD-0037-2016-1.gif /docserver/preview/fulltext/microbiolspec/4/5/MCHD-0037-2016-2.gif
  • Abstract:

    Macrophages exert multiple important roles in iron metabolism. As scavengers, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recycle iron, predominantly for the production of hemoglobin in new erythrocytes. Splenic red pulp macrophages are specialized for iron recycling, with increased expression of proteins for the uptake of hemoglobin, breakdown of heme, and export of iron. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. As regulators and effectors of antimicrobial host defense, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. Macrophages also have an important trophic role in the bone marrow, supporting efficient erythropoiesis.

  • Citation: Ganz T. 2016. Macrophages and Iron Metabolism. Microbiol Spectrum 4(5):MCHD-0037-2016. doi:10.1128/microbiolspec.MCHD-0037-2016.

Key Concept Ranking

Tumor Necrosis Factor alpha
0.43064514
0.43064514

References

1. Ganz T. 2012. Macrophages and systemic iron homeostasis. J Innate Immun 4:446–453. [PubMed][CrossRef]
2. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC. 2005. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200. [PubMed][CrossRef]
3. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093. [PubMed][CrossRef]
4. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY. 2006. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539. [PubMed][CrossRef]
5. Corradini E, Rozier M, Meynard D, Odhiambo A, Lin HY, Feng Q, Migas MC, Britton RS, Babitt JL, Fleming RE. 2011. Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe. Gastroenterology 141:1907–1914. [PubMed][CrossRef]
6. Johnson EE, Wessling-Resnick M. 2012. Iron metabolism and the innate immune response to infection. Microbes Infect 14:207–216. [PubMed][CrossRef]
7. Barber MF, Elde NC. 2014. Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 346:1362–1366. [PubMed][CrossRef]
8. Kim A, Fung E, Parikh SG, Valore EV, Gabayan V, Nemeth E, Ganz T. 2014. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 123:1129–1136. [PubMed][CrossRef]
9. Rodriguez R, Jung CL, Gabayan V, Deng JC, Ganz T, Nemeth E, Bulut Y, Roy CR. 2014. Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun 82:745–752. [PubMed][CrossRef]
10. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271–1276. [PubMed][CrossRef]
11. Barton JC, Acton RT. 2009. Hemochromatosis and Vibrio vulnificus wound infections. J Clin Gastroenterol 43:890–893. [PubMed][CrossRef]
12. Frank KM, Schneewind O, Shieh WJ. 2011. Investigation of a researcher’s death due to septicemic plague. N Engl J Med 364:2563–2564. [PubMed][CrossRef]
13. Bergmann TK, Vinding K, Hey H. 2001. Multiple hepatic abscesses due to Yersinia enterocolitica infection secondary to primary haemochromatosis. Scand J Gastroenterol 36:891–895. [PubMed][CrossRef]
14. Höpfner M, Nitsche R, Rohr A, Harms D, Schubert S, Fölsch UR. 2001. Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis. Scand J Gastroenterol 36:220–224. [PubMed][CrossRef]
15. 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. [PubMed][CrossRef]
16. Beaumont C, Delaby C. 2009. Recycling iron in normal and pathological states. Semin Hematol 46:328–338. [PubMed][CrossRef]
17. Kondo H, Saito K, Grasso JP, Aisen P. 1988. Iron metabolism in the erythrophagocytosing Kupffer cell. Hepatology 8:32–38. [PubMed][CrossRef]
18. Lang F, Qadri SM. 2012. Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif 33:125–130. [PubMed][CrossRef]
19. Buffet PA, Safeukui I, Deplaine G, Brousse V, Prendki V, Thellier M, Turner GD, Mercereau-Puijalon O. 2011. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood 117:381–392. [PubMed][CrossRef]
20. Low PS, Waugh SM, Zinke K, Drenckhahn D. 1985. The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science 227:531–533. [PubMed][CrossRef]
21. Lee SJ, Park SY, Jung MY, Bae SM, Kim IS. 2011. Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver. Blood 117:5215–5223. [PubMed][CrossRef]
22. Pantaleo A, Giribaldi G, Mannu F, Arese P, Turrini F. 2008. Naturally occurring anti-band 3 antibodies and red blood cell removal under physiological and pathological conditions. Autoimmun Rev 7:457–462. [PubMed][CrossRef]
23. Bosman GJCG, Werre JM, Willekens FLA, Novotný VM. 2008. Erythrocyte ageing in vivo and in vitro: structural aspects and implications for transfusion. Transfus Med 18:335–347. [PubMed][CrossRef]
24. Ravichandran KS. 2010. Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207:1807–1817. [PubMed][CrossRef]
25. Föller M, Huber SM, Lang F. 2008. Erythrocyte programmed cell death. IUBMB Life 60:661–668. [PubMed][CrossRef]
26. Mohandas N, An X. 2012. Malaria and human red blood cells. Med Microbiol Immunol (Berl) 201:593–598. [PubMed][CrossRef]
27. Poss KD, Tonegawa S. 1997. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A 94:10919–10924. [PubMed][CrossRef]
28. Kovtunovych G, Eckhaus MA, Ghosh MC, Ollivierre-Wilson H, Rouault TA. 2010. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood 116:6054–6062. [PubMed][CrossRef]
29. Korolnek T, Hamza I. 2015. Macrophages and iron trafficking at the birth and death of red cells. Blood 125:2893–2897. [PubMed][CrossRef]
30. Soe-Lin S, Apte SS, Mikhael MR, Kayembe LK, Nie G, Ponka P. 2010. Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. Exp Hematol 38:609–617. [PubMed][CrossRef]
31. White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK, Campagna D, Hall C, Bishop K, Calicchio ML, Lapierre A, Ward DM, Liu P, Fleming MD, Hamza I. 2013. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17:261–270. [PubMed][CrossRef]
32. Radhakrishnan N, Yadav SP, Sachdeva A, Pruthi PK, Sawhney S, Piplani T, Wada T, Yachie A. 2011. Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J Pediatr Hematol Oncol 33:74–78. [PubMed][CrossRef]
33. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. 1999. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129–135. [PubMed][CrossRef]
34. Nielsen MJ, Møller HJ, Moestrup SK. 2010. Hemoglobin and heme scavenger receptors. Antioxid Redox Signal 12:261–273. [PubMed][CrossRef]
35. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK. 2001. Identification of the haemoglobin scavenger receptor. Nature 409:198–201. [PubMed][CrossRef]
36. Hvidberg V, Maniecki MB, Jacobsen C, Højrup P, Møller HJ, Moestrup SK. 2005. Identification of the receptor scavenging hemopexin-heme complexes. Blood 106:2572–2579. [PubMed][CrossRef]
37. Kohyama M, Ise W, Edelson BT, Wilker PR, Hildner K, Mejia C, Frazier WA, Murphy TL, Murphy KM. 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318–321. [PubMed][CrossRef]
38. Delaby C, Pilard N, Puy H, Canonne-Hergaux F. 2008. Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J 411:123–131. [PubMed][CrossRef]
39. Igarashi K, Sun J. 2006. The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. Antioxid Redox Signal 8:107–118. [PubMed][CrossRef]
40. Hintze KJ, Katoh Y, Igarashi K, Theil EC. 2007. Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, β-globin, and NADP(H) quinone (oxido) reductase1. J Biol Chem 282:34365–34371. [PubMed][CrossRef]
41. Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, Muckenthaler MU. 2010. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 95:1261–1268. [PubMed][CrossRef]
42. Muckenthaler MU, Galy B, Hentze MW. 2008. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28:197–213. [PubMed][CrossRef]
43. Sangokoya C, Doss JF, Chi JT. 2013. Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. PLoS Genet 9:e1003408. doi:10.1371/journal.pgen.1003408. [PubMed][CrossRef]
44. Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, Smith A, Nath KA, Hebbel RP, Vercellotti GM. 2014. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123:377–390. [PubMed][CrossRef]
45. Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. 2014. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol 5:61. doi:10.3389/fphar.2014.00061. [PubMed]
46. Vinchi F, Costa da Silva M, Ingoglia G, Petrillo S, Brinkman N, Zuercher A, Cerwenka A, Tolosano E, Muckenthaler MU. 2016. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127:473–486. [PubMed][CrossRef]
47. Soe-Lin S, Sheftel AD, Wasyluk B, Ponka P. 2008. Nramp1 equips macrophages for efficient iron recycling. Exp Hematol 36:929–937. [PubMed][CrossRef]
48. Shi H, Bencze KZ, Stemmler TL, Philpott CC. 2008. A cytosolic iron chaperone that delivers iron to ferritin. Science 320:1207–1210. [PubMed][CrossRef]
49. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, Bruick RK, Philpott CC. 2011. Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Cell Metab 14:647–657. [PubMed][CrossRef]
50. Yanatori I, Yasui Y, Tabuchi M, Kishi F. 2014. Chaperone protein involved in transmembrane transport of iron. Biochem J 462:25–37. [PubMed][CrossRef]
51. Taniguchi R, Kato HE, Font J, Deshpande CN, Wada M, Ito K, Ishitani R, Jormakka M, Nureki O. 2015. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat Commun 6:8545. doi:10.1038/ncomms9545. [PubMed][CrossRef]
52. Marques L, Auriac A, Willemetz A, Banha J, Silva B, Canonne-Hergaux F, Costa L. 2012. Immune cells and hepatocytes express glycosylphosphatidylinositol-anchored ceruloplasmin at their cell surface. Blood Cells Mol Dis 48:110–120. [PubMed][CrossRef]
53. Cherukuri S, Tripoulas NA, Nurko S, Fox PL. 2004. Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice. Blood Cells Mol Dis 33:346–355. [PubMed][CrossRef]
54. Brissot P, Ropert M, Le Lan C, Loréal O. 2012. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 1820:403–410. [PubMed][CrossRef]
55. Breuer W, Ronson A, Slotki IN, Abramov A, Hershko C, Cabantchik ZI. 2000. The assessment of serum nontransferrin-bound iron in chelation therapy and iron supplementation. Blood 95:2975–2982. [PubMed]
56. Delaby C, Rondeau C, Pouzet C, Willemetz A, Pilard N, Desjardins M, Canonne-Hergaux F. 2012. Subcellular localization of iron and heme metabolism related proteins at early stages of erythrophagocytosis. PLoS One 7:e42199. doi:10.1371/journal.pone.0042199. [PubMed][CrossRef]
57. Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P. 2006. Comparative studies of duodenal and macrophage ferroportin proteins. Am J Physiol Gastrointest Liver Physiol 290:G156–G163. [PubMed][CrossRef]
58. Vidal S, Gros P, Skamene E. 1995. Natural resistance to infection with intracellular parasites: molecular genetics identifies Nramp1 as the Bcg/Ity/Lsh locus. J Leukoc Biol 58:382–390. [PubMed]
59. Alter-Koltunoff M, Goren S, Nousbeck J, Feng CG, Sher A, Ozato K, Azriel A, Levi BZ. 2008. Innate immunity to intraphagosomal pathogens is mediated by interferon regulatory factor 8 (IRF-8) that stimulates the expression of macrophage-specific Nramp1 through antagonizing repression by c-Myc. J Biol Chem 283:2724–2733. [PubMed][CrossRef]
60. Wessling-Resnick M. 2015. Nramp1 and other transporters involved in metal withholding during infection. J Biol Chem 290:18984–18990. [PubMed][CrossRef]
61. Forbes JR, Gros P. 2003. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102:1884–1892. [PubMed][CrossRef]
62. Techau ME, Valdez-Taubas J, Popoff JF, Francis R, Seaman M, Blackwell JM. 2007. Evolution of differences in transport function in Slc11a family members. J Biol Chem 282:35646–35656. [PubMed][CrossRef]
63. Goswami T, Bhattacharjee A, Babal P, Searle S, Moore E, Li M, Blackwell JM. 2001. Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter. Biochem J 354:511–519. [PubMed][CrossRef]
64. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, Hainzl A, Schatz S, Qi Y, Schlecht A, Weiss JM, Wlaschek M, Sunderkötter C, Scharffetter-Kochanek K. 2011. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 121:985–997. [PubMed][CrossRef]
65. Kaempfer T, Duerst E, Gehrig P, Roschitzki B, Rutishauser D, Grossmann J, Schoedon G, Vallelian F, Schaer DJ. 2011. Extracellular hemoglobin polarizes the macrophage proteome toward Hb-clearance, enhanced antioxidant capacity and suppressed HLA class 2 expression. J Proteome Res 10:2397–2408. [PubMed][CrossRef]
66. Nix RN, Altschuler SE, Henson PM, Detweiler CS. 2007. Hemophagocytic macrophages harbor Salmonella enterica during persistent infection. PLoS Pathog 3:e193. doi:10.1371/journal.ppat.0030193. [CrossRef]
67. Soares MP, Weiss G. 2015. The Iron age of host-microbe interactions. EMBO Rep 16:1482–1500. [PubMed][CrossRef]
68. Michels K, Nemeth E, Ganz T, Mehrad B. 2015. Hepcidin and host defense against infectious diseases. PLoS Pathog 11:e1004998. doi:10.1371/journal.ppat.1004998. [PubMed][CrossRef]
69. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EM, Beutler E, Beutler B. 2008. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320:1088–1092. [PubMed][CrossRef]
70. Zohn IE, De Domenico I, Pollock A, Ward DM, Goodman JF, Liang X, Sanchez AJ, Niswander L, Kaplan J. 2007. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 109:4174–4180. [PubMed][CrossRef]
71. Lesbordes-Brion JC, Viatte L, Bennoun M, Lou DQ, Ramey G, Houbron C, Hamard G, Kahn A, Vaulont S. 2006. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108:1402–1405. [PubMed][CrossRef]
72. Altamura S, Kessler R, Gröne HJ, Gretz N, Hentze MW, Galy B, Muckenthaler MU. 2014. Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload. Cell Metab 20:359–367. [PubMed][CrossRef]
73. Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ. 2008. Adherence to macrophages in erythroblastic islands enhances erythroblast proliferation and increases erythrocyte production by a different mechanism than erythropoietin. Blood 111:1700–1708. [PubMed][CrossRef]
74. An X, Mohandas N. 2011. Erythroblastic islands, terminal erythroid differentiation and reticulocyte maturation. Int J Hematol 93:139–143. [PubMed][CrossRef]
microbiolspec.MCHD-0037-2016.citations
cm/4/5
content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0037-2016
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0037-2016
2016-10-21
2017-04-30

Abstract:

Macrophages exert multiple important roles in iron metabolism. As scavengers, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recycle iron, predominantly for the production of hemoglobin in new erythrocytes. Splenic red pulp macrophages are specialized for iron recycling, with increased expression of proteins for the uptake of hemoglobin, breakdown of heme, and export of iron. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. As regulators and effectors of antimicrobial host defense, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. Macrophages also have an important trophic role in the bone marrow, supporting efficient erythropoiesis.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error