Ferroportin, the only mammalian iron exporter identified to date, is highly expressed in duodenal enterocytes and in macrophages. Several lines of evidence indicate that in enterocytes the iron export mediated by ferroportin occurs and is regulated at the basolateral cell surface, where the transporter is strongly expressed. By contrast, in macrophages, ferroportin has been shown in intracellular vesicles. We used a high-affinity antibody to specify the localization of endogenous ferroportin expressed in primary culture of bone marrow-derived macrophages, in both basal and induced conditions. Our observations indicate that ferroportin is expressed in vesicular compartments that can reach the plasma membrane of macrophages. Of importance, when ferroportin expression was up-regulated through iron treatment or erythrophagocytosis, ferroportin expression was strongly enhanced at the plasma membrane of macrophages. Moreover, hepcidin dramatically reduced macrophage ferroportin protein levels. At the subcellular level, hepcidin was shown to induce rapid internalization and degradation of the macrophage iron exporter. These data are consistent with a direct iron export by ferroportin through the plasma membrane of macrophages and strongly support an efficient posttranscriptional down-regulation of ferroportin by hepcidin in these cells. [metal transporter protein-1], Slc40a1) is the sole iron exporter identified in mammals 1-3 that participates in iron release from both enterocytes of the duodenum and tissue macrophages. Ferroportin is highly expressed in absorptive duodenal enterocytes where it presents a strong basolateral subcellular localization 1-3 and in tissue macrophages in liver (Kupffer cells), spleen, and bone marrow. 1,4,5 Several lines of evidence highlight the importance of this protein in iron homeostasis. Inactivation of the ferroportin gene at the adult stage in mice leads to iron accumulation in enterocytes, Kupffer cells, and splenic macrophages. 6 Ferroportin mutations in human patients with type 4 hemochromatosis induce predominant macrophage iron overload. 7 Finally, ferroportin overexpressed in the macrophage cell line J774 stimulates iron release after erythrophagocytosis. 8 Recently, ferroportin has been shown to be the molecular target of hepcidin. 9 Hepcidin is a major systemic regulator of intestinal iron absorption and iron recycling from macrophages. 10 In epithelial cells, hepcidin was shown to act on the efflux of iron through a direct interaction with ferroportin at the cell surface, leading to internalization and degradation of the iron exporter. 9 Moreover, recent studies have shown that some hemochromatosis-associated ferroportin mutations are unresponsive to hepcidin-mediated internalization. [11][12][13] Of interest, in hepcidin-deficient mice, 14 ferroportin is strongly up-regulated in both enterocytes and macrophages. 15 Hepcidin is also assumed to regulate iron efflux from macrophages 10 because it has been shown that treatment of J774 macrophages with hepcidin decreases ferropo...

Tissue macrophages play an essential role in iron recycling through the phagocytosis of senescent RBCs (red blood cells). Following haem catabolism by HO1 (haem oxygenase 1), they recycle iron back into the plasma through the iron exporter Fpn (ferroportin). We previously described a cellular model of EP (erythrophagocytosis), based on primary cultures of mouse BMDMs (bone-marrow-derived macrophages) and aged murine RBCs, and showed that EP induces changes in the expression profiles of Fpn and HO1. In the present paper, we demonstrate that haem derived from human or murine RBCs or from an exogenous source of haem led to marked transcriptional activation of the Fpn and HO1 genes. Iron released from haem catabolism subsequently stimulated the Fpn mRNA and protein expression associated with localization of the transporter at the cell surface, which probably promotes the export of iron into the plasma. These findings highlight a dual mechanism of Fpn regulation in BMDMs, characterized by early induction of the gene transcription predominantly mediated by haem, followed by iron-mediated post-transcriptional regulation of the exporter.

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