UCLA

Reticuloendothelial macrophages of the spleen, liver, blood, and bone marrow are responsible for recycling approximately 25 mg of iron from senescent red blood cells each day to provide iron for erythropoiesis. The female sex hormone, estradiol, is thought to influence iron homeostasis in females, yet there is little mechanistic data linking estrogen signaling to macrophage iron metabolism. To investigate this relationship, we crossed floxed Esr1 and LysM-Cre transgenic animals to excise estrogen receptor alpha/ERα in the myeloid lineage. Female myeloid-specific ERα knockout/MACER mice have reduced red blood cell counts, hemoglobin, and serum iron levels compared to control females. We observed a concomitant increase in the splenic and hepatic iron content of MACER mice and confirmed the presence of iron deposits in the red pulp zone of the spleen. MACER spleens have normal red pulp macrophage staining, which implies that these mice are capable of clearing senescent red blood cells. However, there are significant alterations in iron metabolism gene expression in MACER splenocytes that are consistent with iron accumulation. Macrophages express high levels of ferroportin and ferritin under iron overload conditions to facilitate the export and storage of excess iron, respectively. We also observed elevated hemoxygenase 1 expression in MACER spleens, which catabolizes free heme to avoid heme-related toxicity. The gene expression profiles suggest that free iron and heme accumulate in MACER red pulp macrophages following the phagocytosis of senescent red blood cells and hemoglobin breakdown. Defects in iron recycling limit iron availability for erythropoiesis in the bone marrow and cause peripheral iron storage and low serum iron levels similar to what we observe in MACER mice. We hypothesize that ERα signaling facilitates the release of iron from reticuloendothelial macrophages and that macrophage ERα deletion inhibits erythropoiesis and causes anemia. In conclusion, our data support a novel role for macrophage ERα in iron metabolism and systemic iron homeostasis.