Iron Regulation: Macrophages in Control

Abstract

Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, Kupffer cells in the liver, and central nurse macrophages in the bone marrow ensure a coordinated metabolism of iron to support erythropoiesis. Phagocytosis of senescent red blood cells by macrophages in the spleen and the liver provide a continuous delivery of recycled iron under steady-state conditions and during anemic stress. Central nurse macrophages in the bone marrow utilize this iron and provide a cellular scaffold and niche to promote differentiation of erythroblasts. This review focuses on the role of the distinct macrophage populations that contribute to efficient iron metabolism and highlight important cellular and systemic mechanisms involved in iron-regulating processes.

Keywords: Kupffer cell; central nurse macrophage; erythroblastic islands; erythrophagocytosis; erythropoiesis; inflammation; iron metabolism; macrophage; red pulp macrophage.

Figure 1

Iron metabolism by macrophages. General steps of iron uptake, acquisition, storage and release in the macrophage: In addition to iron extraction from red blood cells by erythrophagocytosis, macrophages express a variety of receptors to acquire iron from different sources. Transferrin-bound iron can be taken up by the transferrin receptor (TfR or CD71) and the complex is internalized by clathrin coated endocytosis followed by iron release at a low endosomal pH. Empty apo-transferrin and transferrin receptor complex are recycled again (grey arrows). Non-transferrin iron can be acquired directly via divalent metal transporter 1 (DMT-1) that is associated with duodenal cytochrome B (DcytB) (blue arrow). CD91 (LRP1) receptors scavenge hemopexin-bound heme (Hpx-Heme) iron, whereas haptoglobin- hemoglobin (Hp-Hgb) complex is taken up through CD163 receptor (red arrows). Iron transport across the endosomal membrane into the cytosol is accomplished through DMT1 after it is reduced by the endosomal reductase six-transmembrane epithelial antigen of the prostate 3 (STEAP3). The resulting intracellular free iron joins the labile iron pool (LIP), which is then either stored in ferritin or utilized in cellular processes for example in mitochondrial iron metabolism as ISC [Fe-S] after being transported through Mitoferrin 1/2 (Mfrn1/2). Iron can be exported through ferroportin 1 (FPN1) out of the cell, supported by the ferroxidase ceruloplasmin (Cp). Iron is then loaded to transferrin in order to be carried to the target cells.

Figure 2

Main regulatory mechanisms of iron. Regulation of iron metabolism through hepcidin, the IRP/IRE, Spi-C/Bach1, and HIF/HRE. For details see text.

Figure 3

Macrophages in erythrophagocytosis and erythropoiesis. The majority of iron in a macrophage is obtained during erythrophagocytosis. Splenic red pulp macrophages (RPMs) and liver Kupffer cells (KCs) is the main source of iron in the body. Senescent red blood cells (RBCs) are recognized by macrophages and digested in the lysosomes. Heme is extracted in the phagolysosomes and transferred to the cytosol by heme transporters heme-carrier protein 1 (HCP1) and heme responsive gene 1 protein (HRG1). Heme degradation by heme oxygenase 1 (HMOX1) in the cytosol provides ferrous iron that enters the intracellular labile iron pool. Iron is either stored in ferritin or exported by ferroportin 1 (FPN1) and ceruloplasmin (Cp). The transcription factor (Spi-C) protects iron processing RPMs in the spleen and BM nurse macrophages. Central nurse macrophages in the bone marrow (BM) promote erythropoiesis in the erythroblastic island niche. These macrophages ubiquitously express transferrin receptors and thus, probably mainly utilize transferrin (Tf)-bound iron. Nurse macrophages are important for the development of erythroblasts. This is mediated by adhesion molecules that control proliferation and differentiation of erythroblasts, enable erythroblast nuclei ingestion, and control the subsequent release of reticulocytes into the blood stream. Central macrophages are supposed to be involved in supplying maturing erythrocytes with iron to trigger heme synthesis.