Decreasing TfR1 expression reverses anemia and hepcidin suppression in β-thalassemic mice

Huihui Li, Tenzin Choesang, Weili Bao, Huiyong Chen, Maria Feola, Daniel Garcia-Santos, Jie Li, Shuming Sun, Antonia Follenzi, Petra Pham, Jing Liu, Jinghua Zhang, Prem Ponka, Xiuli An, Narla Mohandas, Robert E. Fleming, Stefano Rivella, Guiyuan Li and Yelena Z. Ginzburg

Key Points

  • Apotransferrin decreases TfR1 expression and alters TfR1 trafficking to normalize enucleation in β-thalassemic erythroid precursors.

  • Decreased TfR1 upregulates hepcidin in an iron- and ERFE-independent manner, resulting in iron-restricted β-thalassemic erythropoiesis.


Iron availability for erythropoiesis and its dysregulation in β-thalassemia are incompletely understood. We previously demonstrated that exogenous apotransferrin leads to more effective erythropoiesis, decreasing erythroferrone (ERFE) and derepressing hepcidin in β-thalassemic mice. Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for cellular iron delivery during erythropoiesis. We hypothesize that apotransferrin’s effect is mediated via decreased TfR1 expression and evaluate TfR1 expression in β-thalassemic mice in vivo and in vitro with and without added apotransferrin. Our findings demonstrate that β-thalassemic erythroid precursors overexpress TfR1, an effect that can be reversed by the administration of exogenous apotransferrin. In vitro experiments demonstrate that apotransferrin inhibits TfR1 expression independent of erythropoietin- and iron-related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation of defective β-thalassemic erythroid precursors. These findings strongly suggest that overexpressed TfR1 may play a regulatory role contributing to iron overload and anemia in β-thalassemic mice. To evaluate further, we crossed TfR1+/− mice, themselves exhibiting iron-restricted erythropoiesis with increased hepcidin, with β-thalassemic mice. Resultant double-heterozygote mice demonstrate long-term improvement in ineffective erythropoiesis, hepcidin derepression, and increased erythroid enucleation in relation to β-thalassemic mice. Our data demonstrate for the first time that TfR1+/− haploinsufficiency reverses iron overload specifically in β-thalassemic erythroid precursors. Taken together, decreasing TfR1 expression during β-thalassemic erythropoiesis, either directly via induced haploinsufficiency or via exogenous apotransferrin, decreases ineffective erythropoiesis and provides an endogenous mechanism to upregulate hepcidin, leading to sustained iron-restricted erythropoiesis and preventing systemic iron overload in β-thalassemic mice.

  • Submitted September 26, 2016.
  • Accepted January 12, 2017.
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