Macrophages and systemic iron homeostasis

Abstract

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.

Fig. 1

Flow of iron in macrophages. Macrophages take up iron through erythrophagocytosis of damaged or senescent erythrocytes. Macrophages can also scavenge heme and hemoglobin, usually complexed with hemopexin and haptoglobin, respectively, and endocytosed by CD163 and CD91, respectively. Whether phagocytosed in erythrocytes or endocytosed by scavenging, hemoglobin undergoes proteolysis to release heme. Heme is degraded by HO-1 to release iron, which is exported to the cytoplasm by DMT1 and probably also by Nramp1. Cytoplasmic chaperones of the poly(rC) binding protein (PCBP) family deliver iron for storage in ferritin. Alternatively, iron from endosomes or phagolysosomes may also be delivered by an unknown carrier to ferroportin (Fpn) for export. When demand for iron is high, ferritin is degraded by lysosomes or proteasomes, and the released ferrous iron is exported through ferroportin. The rate of iron export is controlled by extracellular hepcidin through its ability to induce the endocytosis and proteolysis of ferroportin. The ferroxidase ceruloplasmin oxidizes iron to its ferric form and thereby facilitates iron export and loading onto the carrier protein transferrin.