Decreasing TfR1 expression reverses anemia and hepcidin suppression in β-thalassemic mice.
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.
Hunan Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China.|Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
Huihui
H
Li
Erythropoiesis Laboratory, New York Blood Center, New York, NY.
Tenzin
T
Choesang
Erythropoiesis Laboratory, New York Blood Center, New York, NY.
Weili
W
Bao
Erythropoiesis Laboratory, New York Blood Center, New York, NY.|State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Huiyong
H
Chen
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.|University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
Maria
M
Feola
Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, QC, Canada.
Daniel
D
Garcia-Santos
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Jie
J
Li
Erythropoiesis Laboratory, New York Blood Center, New York, NY.|State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
Shuming
S
Sun
University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
Antonia
A
Follenzi
Flow Cytometry Core Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
Petra
P
Pham
State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.|Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Jing
J
Liu
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Jinghua
J
Zhang
Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, QC, Canada.
Prem
P
Ponka
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Xiuli
X
An
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Narla
N
Mohandas
Saint Louis University, Saint Louis, MO; and.
Robert E
RE
Fleming
Children's Hospital of Philadelphia, Philadelphia, PA.
Stefano
S
Rivella
Hunan Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China.
Guiyuan
G
Li
Hunan Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China.|Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
Yelena Z
YZ
Ginzburg
D000740:Anemia / Q000209:etiology* / Q000517:prevention & control; D000818:Animals; D001059:Apoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004920:Erythropoiesis; D064451:Hepcidins / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology; D051379:Mice; D011990:Receptors, Transferrin / Q000378:metabolism*; D014168:Transferrin / Q000008:administration & dosage / Q000493:pharmacokinetics; D017086:beta-Thalassemia / Q000378:metabolism*
D001059:Apoproteins; D064451:Hepcidins; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D014168:Transferrin; C028284:apotransferrin