Figure 1.

Macrophage regulation of systemic iron metabolism. Macrophages are central regulators of iron metabolism systemically throughout the body where they regulate largely unidirectional flux of non-transferrin bound iron NTBI, and red blood cell (RBC) erythrophagocytosis. Macrophages across the body and in tumors share similar uptake, storage and release mechanisms. NTBI iron is taken up by ZIP14, and DMT1. RBC are recognized for phagocytosis via CD163, CD91, and CD47 receptors. NTBI is stored as ferritin heavy chain (FTH) and light chain (FTL) complexes. NTBI is released by ferroportin (FPN). In liver Kupffer cells integrate inflammatory cues with NTBI iron recycling to regulate iron homeostasis. Spleen red-pulp macrophages respond to systemic metabolic iron needs by phagocytosis of senescent red blood cells (RBC) and export of recycled NTBI. Bone marrow central macrophages process NTBI received from the periphery to support heme synthesis during erythropoiesis. In the tumor, tumor associated macrophages similarly recycle NTBI and RBC.