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

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.

Iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood

“…Iron deposition score Liver Spleen Duodenum and BKO mice than previously reported values (De Franceschi et al, 2006;Weizer-Stern et al, 2006;Gardenghi et al, 2007;Vogiatzi et al, 2010;Nai et al, 2012;Gelderman et al, 2015;Kautz et al, 2015;Li et al, 2017). However, comparable hematological parameters were also reported in 20-week-old WT and BKO mice obtained from the same animal facility as our study (Wannasuphaphol et al, 2005).…”

Emerging Therapies

“…As HMCs were reduced, the lifespan of RBCs and total amount of Hb in circulation increased. Additionally, haplo-insufficienct TfR1 mice also resulted in improved erythropoiesis with results closely mirroring findings of exogenous apo-transferrin treatment 41 . Increasing circulating hepcidin and manipulating the hepcidin pathway by targeting its regulators may provide patients with more effective options for iron overload management.…”

Using microarray analysis to identify genes and pathways that regulate fetal hemoglobin levels

“…The expression of TFRC depends on the dominance of anemia over iron overload. Reduced TRFC expression reverses anemia and hepcidin suppression in β‐thalassemic mice, and ineffective erythropoiesis is decreased (Li et al., ). Weizer‐Stern et al.…”