Extrahepatic deficiency of transferrin receptor 2 is associated with increased erythropoiesis independent of iron overload

Abstract

Transferrin receptor 2 (TFR2) is a transmembrane protein expressed mainly in hepatocytes and in developing erythroid cells and is an important focal point in systemic iron regulation. Loss of TFR2 function results in a rare form of the iron-overload disease hereditary hemochromatosis. Although TFR2 in the liver has been shown to be important for regulating iron homeostasis in the body, TFR2's function in erythroid progenitors remains controversial. In this report, we analyzed TFR2-deficient mice in the presence or absence of iron overload to distinguish between the effects caused by a high iron load and those caused by loss of TFR2 function. Analysis of bone marrow from TFR2-deficient mice revealed a reduction in the early burst-forming unit–erythroid and an expansion of late-stage erythroblasts that was independent of iron overload. Spleens of TFR2-deficient mice displayed an increase in colony-forming unit–erythroid progenitors and in all erythroblast populations regardless of iron overload. This expansion of the erythroid compartment coincided with increased erythroferrone (ERFE) expression and serum erythropoietin (EPO) levels. Rescue of hepatic TFR2 expression normalized hepcidin expression and the total cell count of the bone marrow and spleen, but it had no effect on erythroid progenitor frequency. On the basis of these results, we propose a model of TFR2's function in murine erythropoiesis, indicating that deficiency in this receptor is associated with increased erythroid development and expression of EPO and ERFE in extrahepatic tissues independent of TFR's role in the liver.

Transferrin Receptors in Erythropoiesis

“…A delayed differentiation of human primary erythroblasts knocked down for TFR2 expression and a decreased sensibility to Epo of murine erythroid progenitors CFU-E from Tfr2 −/− mice were observed [ 10 ]. Following this study, contradictory observations were made in mouse models, with the knockout of Tfr2 leading either to a greater production of RBCs [ 57 , 58 ], or to a decreased production [ 59 , 60 ]. Recently, several studies explored the effect of erythroid Tfr2 deletion in bone-marrow specific deletion models with once again varying results.…”

Iron and platelets: A subtle, under‐recognized relationship

“…27 Furthermore, using a systemic TFR2 deficient mouse model, Wortham et al recently showed that extrahepatic (bone marrow and spleen) TFR2 deficiency was associated with increased erythropoiesis, independent of iron overload. 28 The preferential orientation, in iron deficiency, toward the production of platelets instead of red blood cells remains to be explained. This regulatory mechanism may, on a chronic basis, preserve the use of iron for functions other than erythroid differentiation and, in acute clinical situations, help stop a life-threatening hemorrhage.…”

“…Nevertheless, it has been shown that specific bone marrow TFR2 loss of function stimulates erythropoiesis without causing systemic body iron excess 27 . Furthermore, using a systemic TFR2 deficient mouse model, Wortham et al recently showed that extrahepatic (bone marrow and spleen) TFR2 deficiency was associated with increased erythropoiesis, independent of iron overload 28 . The preferential orientation, in iron deficiency, toward the production of platelets instead of red blood cells remains to be explained.…”

Erythropoietin regulation of red blood cell production: from bench to bedside and back

“…In contrast, hematopoietic-specific ablation of the Tfr2 gene in mice enhances erythropoiesis, likely by modulating EPO sensitivity 102 . Expression of TFR2 in the kidney may inhibit EPO production 103 . Interaction with iron-bound transferrin stabilizes TFR2 at the cell surface 104 , representing a potential mechanism by which TFR2 coordinates erythropoietic rate and enteral iron uptake with circulating iron level.…”