The normal lifespan of erythrocytes is approximately 120 days. During their time in the bloodstream, RBCs undergo progressive modifications (oxidant damage, metabolic depletion, increasing intra cellular calcium concentrations, dehydration, decrease in cell volume, phosphatidylserine exposure, formation of “senescent” antigens, and others) that lead to their selective removal by specialized recycling macrophages in the liver, and spleen (Fig. 1). Macrophages in the bone marrow also cull defective immature erythroid cells to pre vent their release into the circulation and remove some deposits of erythrocyte ferritin from developing RBCs.

Fig1. RECYCLING OF ERYTHROCYTE IRON BY MACROPHAGES. Most erythrocyte iron is acquired by erythrophagocytosis of senescent red blood cells, but smaller amounts are derived from hemoglobin–haptoglobin and heme–hemopexin complexes. Iron derived from plasma transferrin is a minor portion of the total iron flux. Heme is catabolized, and the iron is exported through ferroportin and oxidized by ceruloplasmin. In the absence of iron deficiency, a portion of the iron is retained as ferritin and hemosiderin. See text for details. DMT1, Divalent metal transporter 1; Fe2 Tf, diferric transferrin; FLVCR, feline leukemia virus subgroup C cellular receptor; Hb, hemoglobin; HO-1, heme oxygenase-1; RBC, red blood cells; Tf, transferrin; TfR1, transferrin receptor 1; HRG1: heme importer; STEAP3, six-transmembrane epithelial antigen of the prostate 3. (Modified with permission from Beaumont C, Delaby C. Recycling iron in normal and pathological states. Semin Hematol. 2009;46:328.)

Quality control of RBCs is also performed by the spleen as evidenced after splenectomy by the appearance of abnormal erythrocytes in circulation. On average, each of these iron-recycling macrophages can phagocytize one erythrocyte per day. After ingesting the erythrocyte in a phagosomal vacuole known as an erythrophagolysosome, the erythrocyte membrane is lysed. The hemoglobin within then under goes oxidative precipitation. proteolysis and liberation of heme (see Fig.1). Heme is then transported from the erythrophagolysosome into the cytosol via the heme transporter HRG1 (SLC48A1), a heme transporting permease.

A small proportion of aged or damaged erythrocytes undergo intra vascular hemolysis. With normal erythropoiesis, this portion of the total iron flux is minor but can increase substantially in disorders with increased ineffective erythropoiesis or intravascular hemolysis. The hemoglobin released into plasma is rapidly bound by haptoglobin, a glycoprotein synthesized in the liver. The hemoglobin−haptoglobin complex (Mr 150,000) is too large to be filtered by the kidneys, a feature that helps restrict the renal loss of iron with hemoglobinemia. Macrophages (and hepatocytes; see later) remove the haptoglobin− hemoglobin complex from plasma by binding through the cluster of differentiation 163 (CD163) receptor and after endocytosis digest the complex in lysosomes, liberating heme. In an analogous fashion, any heme released into plasma by intravascular hemolysis complexes with hemopexin and is removed by macrophages (and hepatocytes) expressing the low-density lipoprotein receptor−related protein 1 (LRP1).

In macrophages, heme from all these sources is degraded by an enzymatic complex containing nicotinamide adenine dinucleotide phosphate−cytochrome c reductase, the microsomal enzyme heme oxygenase 1, and biliverdin reductase, yielding carbon monoxide (this is its sole physiologic source in the body), bilirubin, and iron (see Fig. 1). Both DMT1 and natural resistance−associated macro phage protein 1 (NRAMP1; SLC11A1), a DMT expressed within the late endosomal and phagolysosomal membranes of iron-recycling macrophages, seem to be involved in the efficient recycling of this iron. The export of iron from the erythrophagolysosome may occur in parallel with that of heme, considering the evidence that heme export from the macrophage erythrophagolysosome is essential for iron recycling.

Ferroportin is the sole conduit for the export of elemental iron from macrophages in the bone marrow, liver, and spleen to plasma apotransferrin, normally the largest single flux of iron from cells in the body, greatly exceeding the flow of iron from dietary iron absorption in the duodenum. Ferroportin transcription increases in response to both iron and heme. FPN1A levels are also regulated posttranscriptionally through an iron-responsive element in the 5′-untranslated region, with increases in cytosolic iron resulting in increased ferroportin translation. Iron export through ferroportin is facilitated by ferroxidase activity, provided by the multicopper oxidase ceruloplasmin in macrophages and by hephaestin in duodenal enterocytes (see later). Ceruloplasmin oxidation may generate a concentration gradient that helps move the ferric iron out of the macrophage. The ferric iron can then be bound by transferrin and transported back to erythroid and other iron-requiring tissues.

Plasma hepcidin regulates iron efflux from macrophages by decreasing the number of functioning ferroportin molecules available for iron export. The multimeric composition of ferroportin has not been determined definitively, but there is immunohistochemical evidence for a dimeric structure, which is also the simplest explanation for the autosomal dominant inheritance of loss of function ferroportin mutations. For the most part, ferroportin mutations either interfere with iron export by decreasing the amount of functional ferroportin on the cell surface, resulting in retention and accumulation of macrophage iron, or produce ferroportin resistance to internalization and degradation by hepcidin, resulting in loss of control of macrophage iron export that leads to parenchymal iron loading. Following hepcidin binding, conformational change and ubiquitination, ferroportin is degraded after entering the multivesicular body that fuses with lysosomes. Hepcidin can also block the transport function of ferroportin directly by occluding the cavity involved in iron transport. This mechanism may be important in cell types that are not actively endocytic, such as mature erythrocytes.

Under normal circumstances, the macrophages in the liver, spleen, and bone marrow that are specialized in reprocessing hemoglobin iron from senescent erythrocytes partition the recovered iron between storage in ferritin and release through ferroportin. Synthesis of cytosolic ferritin is induced in response to erythrophagocytosis, and in the absence of iron deficiency, some of the iron derived from the ingested erythrocyte is retained within the macrophage inside cytosolic ferritin. With increasing amounts of storage iron within the macrophage, an increasing proportion of iron is stored within amorphous, insoluble masses as hemosiderin.

Iron preparations for intravenous use are carbohydrate-coated iron nanoparticles that are effectively targeted to macrophages. These preparations are relatively nontoxic because the release of iron from these nanoparticles to transferrin is subject to the same regulation as the release of iron from erythrophagocytosis. The use of intravenous iron at high doses would be expected to cause macrophage iron loading which accelerates the synthesis of ferroportin, thereby counter acting the depletion of ferroportin by hepcidin and promoting the export of iron.

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