Systemic iron requirements are met predominantly through the recycling of iron from senescent erythrocytes by macrophages, a process in which the iron exporter ferroportin (Fpn1) is considered to be essential. Yet the role of Fpn1 in macrophage iron recycling and whether it influences innate immune responses are poorly understood in vivo. We inactivated Fpn1 in macrophages by crossing Fpn1-floxed animals with macrophage-targeted LysM-Cre or F4/80-Cre transgenic mice.Macrophage Fpn1 deletion mice were overtly normal; however, they displayed a mild anemia and iron accumulation in splenic, hepatic, and bone marrow macrophages when fed a standard diet. Iron loading was exacerbated after the administration of iron dextran or phenylhydrazine. When Fpn1 LysM/LysM mice were challenged with an iron-deficient diet, they developed a more severe anemia and strikingly higher splenic iron levels than control mice, indicating significantly impaired iron mobilization from macrophages. Because immune responses can be altered by modulating iron status, we also examined the expression of proinflammatory cytokines. We found that expression levels of TNF-␣ and IL-6 were significantly enhanced in Fpn1 LysM/LysM macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses. (Blood. 2011;118(7):1912-1922)

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The liver is a major site of iron storage where sequestered iron can be actively mobilized for utilization when needed elsewhere in the body. Currently, hepatocyte iron efflux mechanisms and their relationships to macrophage iron recycling during the control of whole‐body iron homeostasis are unclear. We hypothesized that the iron exporter, ferroportin1 (Fpn1), is critical for both iron mobilization from hepatocytes and iron recycling from macrophages. To test this, we generated hepatocyte‐specific Fpn1 deletion mice (Fpn1Alb/Alb) and mice that lacked Fpn1 in both hepatocytes and macrophages (Fpn1Alb/Alb;LysM/LysM). When fed a standard diet, Fpn1Alb/Alb mice showed mild hepatocyte iron retention. However, red blood cell (RBC) counts and hemoglobin (Hb) levels were normal, indicating intact erythropoiesis. When fed an iron‐deficient diet, Fpn1Alb/Alb mice showed impaired liver iron mobilization and anemia, with much lower RBC and Hb levels than Fpn1flox/flox mice on the same diet. Using a strategy where mice were preloaded with differing amounts of dietary iron before iron deprivation, we determined that erythropoiesis in Fpn1Alb/Alb and Fpn1flox/flox mice depended on the balance between storage iron and iron demands. On a standard diet, Fpn1Alb/Alb;LysM/LysM mice displayed substantial iron retention in hepatocytes and macrophages, yet maintained intact erythropoiesis, implying a compensatory role for intestinal iron absorption. In contrast, when Fpn1Alb/Alb;LysM/LysM mice were fed an iron‐deficient diet, they developed severe iron‐deficiency anemia, regardless of their iron storage status. Thus, Fpn1 is critical for both hepatocyte iron mobilization and macrophage iron recycling during conditions of dietary iron deficiency. Conclusion: Our data reveal new insights into the relationships between Fpn1‐mediated iron mobilization, iron storage, and intestinal iron absorption and how these processes interact to maintain systemic iron homeostasis. (HEPATOLOGY 2012;56:961–971)