Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Abstract

The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia or other erythropoietic stimuli, and suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is thought to be mediated by interference with paracrine BMP signaling that regulates hepcidin transcription in hepatocytes. In anemias with ineffective erythropoiesis, ERFE is pathologically overproduced but its contribution to the clinical manifestations of these anemias is not well understood. We generated three lines of transgenic mice with graded erythroid overexpression of ERFE and showed that they developed dose-dependent iron overload, impaired hepatic BMP signaling and relative hepcidin deficiency. These findings add to the evidence that ERFE is a mediator of iron overload in conditions where ERFE is overproduced, including anemias with ineffective erythropoiesis. At the highest levels of ERFE overexpression the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive ERFE in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development.

The hepatokine FGL1 regulates hepcidin and iron metabolism during the recovery from hemorrhage-induced anemia in mice

“…One possible explanation would be that, without the rapid (24h) compensatory suppression of hepcidin by ERFE, increased erythropoietic rate and iron consumption by erythroid precursors result in a transient hypoferremia which, in turn, decreases the activation of the BMP/SMAD signaling and hepcidin transcription 40,41 . A comparable observation has been made in Erfe-/-mice subjected to acute 40 or chronic EPO treatment 42 . Another likely possibility is that prolonged anemia and hypoxia stimulate the production of a yet-unidentified repressor of hepcidin.…”

“…Indeed, bone marrow ablation leads to decreased reticulocytes and erythroblasts iron consumption which increases serum iron concentration and transferrin saturation 43 and stimulates the BMP/Smad signaling (Supplemental figure 7-8) and hepcidin expression through the HFE/TFR2 axis 44,45 . Importantly, the iron signal seems dominant over the erythropoietic drive as ERFE is less efficient in repressing hepcidin in iron-loaded WT mice 11,42,46 . Moreover, increased liver Saa1 mRNA expression indicates that the radiation caused an inflammatory response that could also stimulate hepcidin expression through the IL-6/STAT3 or BMP/SMAD signaling [47][48][49] .…”

Managing the Dual Nature of Iron to Preserve Health

“…Erfe is upregulated in erythroid tissues in all conditions characterized by increased serum EPO and expanded erythropoiesis, such as iron deficiency anemia and hypoxia [ 80 ], but also in diseases characterized by ineffective erythropoiesis, such as beta-thalassemia [ 82 ]. Here, excessive ERFE production causes secondary iron overload, as also observed in mice overexpressing Erfe [ 83 ]. However, preclinical models demonstrate that ERFE is relevant in hepcidin downregulation in conditions of acute stress erythropoiesis, but not in chronic conditions [ 84 ], where other mechanism/s are likely involved.…”

Fighting age-related orthopedic diseases: focusing on ferroptosis

“… 110 In contrast, ERFE overexpression resulted in iron overload and developmental abnormalities in mice. 111 Hepcidin expression is also upregulated during inflammation; for instance, interleukin-6 (IL-6) directly regulates hepcidin expression by activating signal converter and activator of transcription 3, 112 and the bone morphogenetic protein signaling pathway is required for IL-6-induced hepcidin expression. 113 …”