Fig. 1

Macrophage Metal Metabolism. This brief summary of the metal metabolism of a generic macrophage highlights several mechanisms by which a macrophage can obtain metals. There are numerous metal transport proteins and receptors involved to ensure an adequate supply of these essential metals to the macrophage. (1) Macrophages obtain iron from various sources. Free circulating iron is first reduced from ferric to ferrous iron and then imported into the macrophage via protein transporters such as DMT1 and ZIP14. Transferrin-bound iron is bound to the transferrin receptor on the cell surface and imported via receptor-mediated endocytosis. Some macrophages also have the ability to obtain iron via erythrophagocytosis while others express receptors such as CD163 and CD64 allowing for the uptake of haemoglobin-haptoglobin and heme-hemopexin complexes, respectively. Once iron enters the macrophage it has numerous fates depending on the activation state of the cell. It can be stored in its ferrous state within the ferritin complex or utilized in the mitochondria for Fe-S cluster and heme biosynthesis. Iron is exported out of the macrophage through the only known iron export protein, ferroportin (FPN) whose expression is regulated by the hormone hepcidin. Further post-transcriptional regulation of intracellular iron levels is carried out by cytosolic regulatory proteins IRP1 and IRP2. (2) Intracellular zinc supply is mediated by two families of transport proteins; SLC39A (ZIPs) import zinc into the cell while SLC30A mediates zinc export out of the cell. (3) The copper importers Ctr1 and ATPase metal pump, ATP7A are two known copper transporters within the macrophage and gets upregulated to facilitate copper mediated host defence mechanisms