Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses

Z Zhang, F Zhang, P An, X Guo, Y Shen… - Blood, The Journal …, 2011 - ashpublications.org
Z Zhang, F Zhang, P An, X Guo, Y Shen, Y Tao, Q Wu, Y Zhang, Y Yu, B Ning, G Nie
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
Abstract
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 Fpn1LysM/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-α and IL-6 were significantly enhanced in Fpn1LysM/LysM macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses.
ashpublications.org