Format

Send to

Choose Destination
Blood. 2017 Mar 16;129(11):1514-1526. doi: 10.1182/blood-2016-09-742387. Epub 2017 Feb 1.

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

Author information

1
Hunan Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China.
2
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
3
Erythropoiesis Laboratory, New York Blood Center, New York, NY.
4
State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
5
University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
6
Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, QC, Canada.
7
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
8
Flow Cytometry Core Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
9
Saint Louis University, Saint Louis, MO; and.
10
Children's Hospital of Philadelphia, Philadelphia, PA.

Abstract

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.

PMID:
28151426
PMCID:
PMC5356456
DOI:
10.1182/blood-2016-09-742387
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center