Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

Abstract

Inherited anemias with ineffective erythropoiesis, such as β-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of HbbTh3/+ mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in β-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of β-thalassemia.

EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

“…In a mouse model for β‐thalassemia intermedia, plasma ERFE levels were massively increased and ERFE messenger RNA levels elevated in the marrow and spleen. Ablation of ERFE in these mice restored hepcidin levels to normal and reduced liver iron content and serum iron concentration, demonstrating that ERFE could be a pathological suppressor of hepcidin in ineffective erythropoiesis 2. However, there is no assay available yet for human plasma.…”

“…In a mouse model, erythroblasts produce ERFE in response to EPO, leading to an increase in plasma ERFE concentration 2. Elevations in ERFE levels suppress hepcidin‐25 synthesis of the liver to allow iron acquisition from absorption and storage sites, favoring recovery from anemia secondary to blood loss.…”

“…We anticipated this 100‐fold dilution would allow the measurement of ERFE levels since the measurement range of the kit is given as 15.6‐1000 pg/mL and concentrations observed in a mouse model of β‐thalassemia intermedia were 10‐25 ng/mL 1. For blood donors, we also included dilutions of 2‐ to 10‐fold based on the assumption that pre‐donation values would be <100 pg/mL as observed for wild‐type mice,1 with a reported 30‐fold increase upon phlebotomy 2b

−0 = measurement at baseline, before donation, −4 = measurement at day 4.

dil, dilutions; NA, not available; ND, not determined; LLOD, lower limit of detection as reported in kit manual: 3.9 pg/mL; sTfR, soluble transferrin receptor.

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“…We anticipated this 100‐fold dilution would allow the measurement of ERFE levels since the measurement range of the kit is given as 15.6‐1000 pg/mL and concentrations observed in a mouse model of β‐thalassemia intermedia were 10‐25 ng/mL 1. For blood donors, we also included dilutions of 2‐ to 10‐fold based on the assumption that pre‐donation values would be <100 pg/mL as observed for wild‐type mice,1 with a reported 30‐fold increase upon phlebotomy 2…”

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

“…ERFE ablation resulted in a more severe anemia with inappropriately elevated hepcidin expression in heat-killed Brucella abortus-induced inflammation anemia [16]. Moreover, ERFE also mediates pathological hepcidin suppression in conditions of ineffective erythropoiesis, such as β-thalassemia [17].…”