Erythron to the Liver: Send Iron

For successful expansion of erythropoiesis, the activity of the hormone erythropoietin (EPO) must be coordinated with the supply of iron to erythroid precursors. Increased iron supply for erythropoiesis is ensured by the suppression of hepcidin, the iron-regulatory hormone produced by the liver. Low hepcidin levels allow greater absorption of dietary iron and greater mobilization of iron from the stores in the spleen and the liver. The mechanisms coordinating erythropoietic activity with iron delivery are not well understood. We recently identified erythroferrone as a new mediator of hepcidin suppression during stress erythropoiesis¹. Erythroferrone (ERFE) is a member of the C1q/TNF-related protein (CTRP) family of metabolic mediators. ERFE is produced in response to EPO by erythroblasts of the bone marrow and spleen of mice. The induction of ERFE by EPO was dependent on Jak2/Stat5 signaling. Ex vivo treatment of human erythroblasts with EPO also resulted in a dramatic induction of ERFE expression. The essential role of ERFE in acute hepcidin suppression by erythropoiesis was demonstrated in ERFE-deficient mice. In contrast to wild-type mice which suppressed hepcidin ~10-fold within hours after hemorrhage or erythropoietin injection, no hepcidin suppression was observed in ERFE knockout mice within 24 h. As a consequence, ERFE-deficient mice exhibited delayed recovery of hemoglobin after hemorrhage or severe inflammation. Treatment of mice or hepatocytes with recombinant ERFE protein confirmed the hepcidin-suppressive activity of the protein. It remains to be seen whether administration of ERFE protein would be useful for the treatment of anemia of inflammation mediated by elevated hepcidin. In iron-loading anemias including β-thalassemia, hepcidin is chronically suppressed by the exuberant but ineffective erythropoietic activity. This is the cause of iron overload in untransfused thalassemia patients and may contribute to iron loading even in transfused patients. We found that ERFE expression is greatly increased in the bone marrow and spleen of mice with β-thalassemia intermedia (th3 model). Transgenic ablation of ERFE in th3 mice normalized hepcidin and partially corrected their iron overload. Although human studies of the role of ERFE in health and disease are clearly needed, ERFE is a promising candidate for the pathological suppressor of hepcidin in anemias with ineffective erythropoiesis.

References:

1. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014; 46: 678-684.