As a principal aspect of their scavenging function, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recover iron, mainly for the production of hemoglobin in new erythrocytes but also for other carriers and enzymes requiring iron. Splenic red pulp macrophages are specialized for iron recycling with increased expression of proteins for the uptake of hemoglobin, breakdown of heme and the export of iron. In humans, recycling macrophages contribute the majority of the iron flux into extracellular fluid, exceeding the contribution of dietary iron absorption and release of stored iron from hepatocytes. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. In addition to their homeostatic role, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. This review discusses the iron-scavenging function of macrophages in the context of iron homeostasis and host defense.

Pollard JW: Trophic macrophages in development and disease. Nat Rev Immunol 2009;9:259–270.
Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC: The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005;1:191–200.
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.
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.
Ganz T, Nemeth E: Hepcidin and disorders of iron metabolism. Annu Rev Med 2011;62:347–360.
Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271–1276.
Frank KM, Schneewind O, Shieh WJ: Investigation of a researcher’s death due to septicemic plague. N Engl J Med 2011;364:2563–2564.
Bergmann TK, Vinding K, Hey H: Multiple hepatic abscesses due to Yersinia enterocolitica infection secondary to primary haemochromatosis. Scand J Gastroenterol 2001;36:891–895.
Barton JC, Acton RT: Hemochromatosis and Vibrio vulnificus wound infections. J Clin Gastroenterol 2009;43:890–893.
Beaumont C, Delaby C: Recycling iron in normal and pathological states. Semin Hematol 2009;46:328–338.
Kondo H, Saito K, Grasso JP, Aisen P: Iron metabolism in the erythrophagocytosing Kupffer cell. Hepatology 1988;8:32–38.
Lang F, Gulbins E, Lang PA, Zappulla D, Foller M: Ceramide in suicidal death of erythrocytes. Cell Physiol Biochem 2010;26:21–28.
Foller M, Huber SM, Lang F: Erythrocyte programmed cell death. IUBMB Life 2008;60:661–668.
Buffet PA, Safeukui I, Deplaine G, Brousse V, Prendki V, Thellier M, Turner GD, Mercereau-Puijalon O: The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood 2011;117:381–392.
Low PS, Waugh SM, Zinke K, Drenckhahn D: The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science 1985;227:531–533.
Pantaleo A, Giribaldi G, Mannu F, Arese P, Turrini F: Naturally occurring anti-band 3 antibodies and red blood cell removal under physiological and pathological conditions. Autoimmun Rev 2008;7:457–462.
Lee SJ, Park SY, Jung MY, Bae SM, Kim IS: Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver. Blood 2011;117:5215–5223.
Bosman GJCG, Willekens FLA, Werre JM: Erythrocyte aging: a more than superficial resemblance to apoptosis? Cell Physiol Biochem 2005;16:1–8.
Ravichandran KS: Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 2010;207:1807–1817.
Williams TN: Red blood cell defects and malaria. Mol Biochem Parasitol 2006;149:121–127.
Poss KD, Tonegawa S: Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 1997;94:10919–10924.
Kovtunovych G, Eckhaus MA, Ghosh MC, Ollivierre-Wilson H, Rouault TA: Dysfunction of the heme recycling system in heme oxygenase-1 deficient mice: effects on macrophage viability and tissue iron distribution. Blood 2010;116:6054–6062.
Radhakrishnan N, Yadav SP, Sachdeva A, Pruthi PK, Sawhney S, Piplani T, Wada T, Yachie A: Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J Pediatr Hematol Oncol 2011;33:74–78.
Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 1999;103:129–135.
Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK: Identification of the haemoglobin scavenger receptor. Nature 2001;409:198–201.
Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK: Identification of the receptor scavenging hemopexin-heme complexes. Blood 2005;106:2572–2579.
Nielsen MJ, Møller HJ, Moestrup SK: Hemoglobin and heme scavenger receptors. Antioxid Redox Signal 2009;12:261–273.
Kohyama M, Ise W, Edelson BT, Wilker PR, Hildner K, Mejia C, Frazier WA, Murphy TL, Murphy KM: Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 2009;457:318–321.
Delaby C, Pilard N, Puy H, Canonne-Hergaux F: Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J 2008;411:123–131.
Cairo G, Locati M, Mantovani G: Control of iron homeostasis as a key component of macrophage polarization. Haematologica 2010;95:1801–1803.
Corna G, Campana L, Pignatti E, Castiglioni A, Tagliafico E, Bosurgi L, Campanella A, Brunelli S, Manfredi AA, Apostoli P, Silvestri L, Camaschella C, Rovere-Querini P: Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 2010;95:1814–1822.
Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D, Cairo G: Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 2010;40:824–835.
Igarashi K, Sun J: The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. Antioxid Redox Signal 2006;8:107–118.
Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, Muckenthaler MU: Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 2010;95:1261–1268.
Hintze KJ, Katoh Y, Igarashi K, Theil EC: Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1. J Biol Chem 2007;282:34365–34371.
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.
Soe-Lin S, Apte SS, Andriopoulos B Jr, Andrews MC, Schranzhofer M, Kahawita T, Garcia-Santos D, Ponka P: Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci USA 2009;106:5960–5965.
Shi H, Bencze KZ, Stemmler TL, Philpott CC: A cytosolic iron chaperone that delivers iron to ferritin. Science 2008;320:1207–1210.
Harris ZL, Durley AP, Man TK, Gitlin JD: Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 1999;96:10812–10817.
Brissot P, Ropert M, Le LC, Loreal O: Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 2011, E-pub ahead of print.
Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F: Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005;106:3979–3984.
Vidal S, Gros P, Skamene E: Natural resistance to infection with intracellular parasites: molecular genetics identifies Nramp1 as the Bcg/Ity/Lsh locus. J Leukoc Biol 1995;58:382–390.
ter-Koltunoff M, Goren S, Nousbeck J, Feng CG, Sher A, Ozato K, Azriel A, Levi BZ: 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 2008;283:2724–2733.
Forbes JR, Gros P: Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 2003;102:1884–1892.
Techau ME, Valdez-Taubas J, Popoff JF, Francis R, Seaman M, Blackwell JM: Evolution of differences in transport function in Slc11a family members. J Biol Chem 2007;282:35646–35656.
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: An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 2011;121:985–997.
Kaempfer T, Duerst E, Gehrig P, Roschitzki B, Rutishauser D, Grossmann J, Schoedon G, Vallelian F, Schaer DJ: Extracellular hemoglobin polarizes the macrophage proteome toward Hb-clearance, enhanced antioxidant capacity and suppressed HLA class 2 expression. J Proteome Res 2011;10:2397–2408.
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