Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

Abstract

Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required.

Systemic iron homeostasis and erythropoiesis

“…In a different approach, bone marrow transplantation from Tfr2–/– mice to isogenic wild type recipients (Tfr2 BMK °) led to similar impairment in erythroid differentiation under milder dietary iron restriction . However, contrary to hematopoietic‐specific Tfr2–/– mice, the chimeric Tfr2 BMK ° animals had increased hemoglobin, higher erythrocyte counts, lower hepcidin expression in the liver, and increased Erfe expression in the bone marrow . These findings are consistent with an inhibitory function of TfR2 on EPO sensitivity.…”

“…In the absence of iron‐loaded transferrin, TfR2 undergoes proteolytic shedding to a soluble inactive form . Mice bearing hematopoietic‐specific ablation of Tfr2 exhibited normal systemic iron homeostasis, but responded to dietary iron restriction with increased extramedullary erythropoiesis in the liver and spleen compared to controls . Furthermore, they accumulated a higher number of immature erythroid cells at the stage of polychromatic erythroblasts, at the expense of mature cells (reticulocytes and erythrocytes).…”

Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice

“…Several recent reports have highlighted the role of transferrin receptor 2 (TFR2) in erythropoiesis [ 32 – 34 ]. Since functional erythropoiesis is compromised in mask mice, it was of interest to compare the expression of splenic Tfr2 mRNA between C57BL/6 and mask mice.…”

“…FAM132A protein (adipolin or CTRP12) is reported to form heteromeric complexes with ERFE in vitro [ 41 ], and could therefore theoretically modulate ERFE-dependent signaling; however, this role of CTRP12 remains so far speculative, as we were unable to confirm its increased levels by immunoblotting. TFR2 protein has recently been demonstrated to play a role not only in the liver, but also in erythroid precursors [ 32 – 34 ], where it might function as a modulator of EPO signaling [ 42 ]. In the case of TFR2, we were able to document the effect of EPO not only at the mRNA level, but, by analyzing splenic microsomes, also at the protein level.…”

Rare anemias due to genetic iron metabolism defects

“…Cells acquire iron bound to transferrin. Soluble transferrin-iron complexes are recognized by two transmembrane receptors, transferrin receptor 1 (TFR1 or TFRC official gene) and transferrin receptor 2 (TFR2 gene) [7][8] [9]. The affinity of TFR2 for iron is dramatically lower than that of TFR1 so that its role in iron uptake is likely minimal compared to TFR1.…”