Model of heme-iron recycling and tissue iron redistribution in HO-1^−/− mice. Splenic macrophages that phagocytose senescent RBCs die in HO-1^−/− mice. The contents released from dying macrophages include nonmetabolized heme, which damages surrounding cells and causes fibrosis in red pulp areas of the spleen, thereby eliminating the normal setting in which recycling of RBCs usually occurs. Senescent RBCs rupture in the circulation, releasing Hb and heme. The liver increases synthesis of Hp and Hpx, but there are few viable macrophages remaining in the spleen and liver that can recycle Hb-Hp complexes through the CD163 receptor. Iron stores shift from liver and splenic macrophages to hepatocytes and kidney proximal tubules where Hb and, perhaps, other heme moieties are reabsorbed, and iron can be recovered from heme by HO-2 enzymatic activity. The intensity of blue coloration represents iron loading as observed by Perls Prussian blue staining. Red and green arrows represent directions of heme and transferrin iron flows, respectively. Black arrows represent flow of proteins, such as Hp and Hpx. The thickness of each particular arrow reflects the proportional flux of transferrin iron, heme iron, and other important molecules, such as Hpx and Hp, as proposed by the model. The difference in spleen size shown in the figure is relevant for HO-1^−/− mice at the age of 9 months and older.