Iron Release from Macrophages after Erythrophagocytosis Is Up-Regulated by Ferroportin 1 Overexpression and Down-Regulated by Hepcidin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 5; pp. 1324 - 1328
• Main Authors: Knutson, Mitchell D., Oukka, Mohamed, Koss, Lindsey M., Aydemir, Fikret, Wessling-Resnick, Marianne, Cousins, Robert J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.02.2005; National Acad Sciences
• Subjects: Animals; Antibodies; Antimicrobial Cationic Peptides - genetics; Biological Sciences; Biology; Cation Transport Proteins - genetics; Cell Line; Cells; Erythrocytes; Erythrocytes - physiology; Ferritins; Gene expression; Gene Expression Regulation; Hepcidins; Humans; Iron; Iron - metabolism; Kupffer cells; Liver; Macrophages; Macrophages - physiology; Mice; Phagocytosis; Phagocytosis - physiology; Proteins; Recycling; Stem cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0409409102

Ferroportin 1 (FPN1) is transmembrane protein involved in iron homeostasis. In the duodenum, FPN1 localizes to the basolateral surface of enterocytes where it appears to export iron out of the cell and into the portal circulation. FPN1 is also abundantly expressed in reticuloendothelial macrophages of the liver, spleen, and bone marrow, suggesting that this protein serves as an iron exporter in cells that recycle iron from senescent red blood cells. To directly test the hypothesis that FPN1 functions in the export of iron after erythrophagocytosis, FPN1 was stably expressed in J774 mouse macrophages by using retroviral transduction, and release of59Fe after phagocytosis of59Fe-labeled rat erythrocytes was measured. J774 cells overexpressing FPN1 released 70% more59Fe after erythrophagocytosis than control cells, consistent with a role in the recycling of iron from senescent red cells. Treatment of cells with the peptide hormone hepcidin, a systemic regulator of iron metabolism, dramatically decreased FPN1 protein levels and significantly reduced the efflux of59Fe after erythrophagocytosis. Subsequent fractionation of the total released59Fe into heme and nonheme compounds revealed that hepcidin treatment reduced the release of nonheme59Fe by 50% and 25% from control and FPN1-overexpressing cells, respectively, but did not diminish efflux of59Fe-heme. We conclude that FPN1 is directly involved in the export of iron during erythrocyte-iron recycling by macrophages.