The liver has emerged as the central regulator of iron homeostasis. It produces the hormone hepcidin, which controls body iron content and the distribution of iron to tissues. Hepcidin controls the major flows of iron into plasma: absorption of dietary iron in intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes. Iron is exported from these tissues into plasma through ferroportin, the sole cellular iron efflux channel and the hepcidin receptor. Hepcidin causes the endocytosis and degradation of ferroportin, leading to the retention of iron in target cells and decreased flow of iron into plasma.
Iron is an essential functional component of heme and hemoglobin. The production of functional erythrocytes therefore depends on the timely delivery of sufficient iron to erythroid precursors. The iron supply to the marrow comes under particular strain after hemorrhage, hemolysis and other states that trigger expanded erythropoiesis. Both the absorption of dietary iron and the release of iron from stores are increased as erythropoiesis intensifies but the cross talks involved in these mechanisms are not known. After loss of erythrocytes from hemorrhage or hemolysis, critical signals facilitating the provision of iron for restorative erythropoiesis are expected to occur within hours, as rapid recovery of red cell mass and oxygen carrying capacity confers obvious evolutionary advantages. Recent advances in our understanding of iron biology allowed us to take a new look at this unsolved puzzle.
The existence of an “erythron-related regulator” that modifies iron absorption to meet the iron requirements of erythropoiesis was proposed in the late 1950s. We recently identified the hormone erythroferrone (ERFE), an orphan member of the C1q-TNF family of proteins, and presented evidence that it is the long-sought erythroid regulator of iron homeostasis (Kautz et al., Nat Genet 2014). ERFE is produced by erythroid precursors in response to erythropoietin, and it acts on the liver to rapidly suppress hepcidin and increase iron absorption. ERFE promotes the recovery from hemorrhage-induced anemia and anemia of inflammation. At the other end of the spectrum, increased production of ERFE causes hepcidin suppression and secondary iron overload in ß-thalassemia. However, nothing is known about the molecular mechanism by which ERFE targets hepatocytes to suppress hepcidin expression and deciphering this mechanism is the subject of this proposal. The basic science portion of this project will identify the receptor(s) for ERFE and the signal transduction pathways for hepcidin regulation.
Delineating the mechanism of hepcidin suppression by ERFE is of high biomedical importance as the pathway could be targeted to develop novel treatments for iron-restricted anemias in which iron and EPO therapies are ineffective because of elevated hepcidin (e.g. infections, anemia of inflammatory bowel disease, cancer, or chronic kidney disease) and for iron-loading anemias (e.g. thalassemias). In the translational portion of this project we will develop an assay to assess the contribution of ERFE in human pathologies. We will identify small molecules that mimic or inhibit ERFE in order to ameliorate anemia and iron overload, respectively. The potential of ERFE or ERFE analogs to treat iron-restrictive anemias, including anemia of inflammation and anemia of chronic kidney diseases, will be tested in mice. Finally, hosts and pathogens compete for iron acquisition in order to ensure critical metabolic functions but how ERFE could interfere with pathogen survival is not currently known. We will therefore investigate the impact of ERFE and its manipulation on the relation host/pathogen.
Monsieur Leon Kautz (Institut National de la Santé et de la Recherche Médicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Inserm (IRSD) Institut National de la Santé et de la Recherche Médicale
Help of the ANR 325,000 euros
Beginning and duration of the scientific project: January 2016 - 48 Months