Molecular liaisons between erythropoiesis and iron metabolism

Abstract

Although most circulating iron in blood plasma is destined for erythropoiesis, the mechanisms by which erythropoietic demand modulates the iron supply (“erythroid regulators”) remain largely unknown. Iron absorption, plasma iron concentrations, and tissue iron distribution are tightly controlled by the liver-produced hormone hepcidin. During the last decade, much progress has been made in elucidating hepcidin regulation by iron and inflammation. This review discusses the less understood mechanisms and mediators of hepcidin suppression in physiologically and pathologically stimulated erythropoiesis.

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

“…Under pathological conditions (e.g. hemorrhage or hemolysis), erythroid precursors request a delivery of sufficient iron in bone marrow for the production of erythrocytes [2,3]. The liver-produced hormone hepcidin is identified as the main circulating regulator of systemic iron balance, and its suppression in anemia might result from hypoxia or EPO [6][7][8].…”

“…Hemolytic anemia could induce stress erythropoiesis in bone marrow and a remarkable alteration of iron homeostasis in order to meet the elevated demand of iron supply for hemoglobin synthesis and erythroid cell maturation [2,3]. Erythropoiesis and iron homeostasis have been proved to regulate each other to ensure an optimal amount of oxygen and iron supply to cells and tissues [4,5].…”

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…There is elevated formation of free radicals and increased oxidative stress in erythroid precursors due to enhanced demand of iron for hemoglobin synthesis and accumulated hemoglobin content [20,66,67], and erythroid precursors may be also subjected to oxidative stress from foreign chemicals including drugs for medicinal purposes and environmental toxicants [19,22,68]. Therefore, erythroid cells are highly sensitive to oxidative stress, and aberrant ROS accumulation incurs impaired erythropoiesis, shortened lifespan of RBCs and even hemolysis [66,69,70].…”

Modern iron replacement therapy: clinical and pathophysiological insights

“…For example, after an acute blood loss hepcidin is suppressed in order to match the increased iron need of erythroid precursors for rapid production of new RBCs. In murine models, a hormone named erythroferrone (ERFE) has been identified as the hepcidin suppressing agent produced by erythroblasts [9,31]. In humans, the ERFE ortologue encoded by the gene FAM132B seems also involved in hepcidin suppression under conditions of increased erythropoiesis [32,33], although in combination with other factors still poorly characterized [23].…”

“…near 2.4 millions per second. Such an impressive activity requires a daily supply of 20-25 mg of iron to erythroid precursors in the bone marrow [9]. The body iron content (~ 4 g in the adult male, ~ 3 g in the female) must be kept constant, to avoid either deficiency or overload, which can also be detrimental by facilitating the production of toxic reactive oxygen species [10].…”