EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia

Abstract

a b s t r a c t a r t i c l e i n f oHemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40 mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2 days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3 days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3 days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPOdependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia.

Erythroferrone and iron status parameters levels in pediatric patients with iron deficiency anemia

“…This study raises questions about this new erythroid hormone and its role in hepcidin suppression in different types of anemia. [10][11][12][13] As there have been no previous reports on the relation between human serum erythroferrone and iron status parameters levels in cases with iron deficiency anemia; the present study aimed to demonstrate the relation between serum erythroferrone and iron status parameters levels in this widespread type of pediatric anemia.…”

“…Erythroferrone is lately identified by Kautz et al as key regulator of iron homeostasis during stress erythropoiesis by suppressing hepcidin expression. This study raises questions about this new erythroid hormone and its role in hepcidin suppression in different types of anemia …”

Mild Hereditary Spherocytosis without Accompanying Hereditary Haemochromatosis: An Unrecognised Cause of Iron Overload

“…Similarly, Jiang et al [8] demonstrated upregulation of erythroferrone in a mouse model of acute haemolytic anaemia. These studies suggest that in EPO-elevated states iron absorption is encouraged via erythroferrone regulation of hepcidin.…”

A computational model to understand mouse iron physiology and diseases

“…Erythroferrone secretion by erythroid precursors is stimulated by elevated EPO levels, and erythroferrone inhibits the secretion of hepcidin -resulting in a negative regulation of hepcidin by EPO. EPO is elevated in conditions that require increased production of RBC, such as after hemorrhage or in anemia, resulting in increased erythroferrone and finally in suppression of hepcidin (Kautz et al, 2015;Kim & Nemeth, 2015;Jiang et al, 2016), allowing iron to be mobilized from the liver and spleen to the plasma, and also increasing dietary iron absorption. This provides the required increased levels of iron for increased RBC production.…”