Erythropoietin (Epo) is the main cytokine controlling terminal erythropoiesis. Twenty years ago a model of erythropoiesis regulation has been described suggesting that the circulating Epo level is suboptimal and only a fraction of erythroid progenitors survives to produce erythrocytes (Koury and Bondurant; Science, 1990). Therefore differential Epo sensitivity would control erythroblasts survival. However, cell autonomous and/or environmental factors controlling this process remain elusive. Erythroblasts highly express the transferrin receptor 1 (TfR1), which has been shown to be essential for iron uptake allowing hemoglobin synthesis. We have previously identified TfR1 as an unsuspected polymeric (p)IgA1 receptor. Here we show that TfR1-bound pIgA1 (but not monomeric (m)IgA1) rescued the growth and clonogenic potential of human erythroblasts under suboptimal Epo concentrations. In a humanized mouse model (α1KI mice) IgA1 polymers increased spleen homeostatic erythropoietic activity and accelerated stress erythropoiesis in several models of anemia (phenylhydrazine and autoimmune hemolytic anemia; 5-fluorouracyl-induced central anemia). By contrast, mice lacking the immunoglobulin joining-(J) chain (α1KI/J-chain−/−), which are devoid of pIgA1 demonstrated a delayed recovery from anemia. Moreover, IgA deficiency patients presented increased Epo levels. Upon hypoxia, pIgA1 levels increased in both humans and mice. Likewise, α1KI mice submitted to chronic intermittent hypoxia presented an enhanced erythroblasts expansion relative to their LT controls. Therefore, hypoxia regulates pIgA1 production and, in turn, pIgA1/TfR1 interaction modulates erythroblast sensitivity to growth factors by decreasing cell activation threshold. We also showed that the natural TfR1 ligand, iron-loaded transferrin (Fe-Tf), also accelerated recovery from acute anemia. At the molecular level, pIgA1 and Fe-Tf converged for Epo-dependent erythroblasts proliferation. TfR1 engagement increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase and phosphatidylinositol-3-kinase signaling pathways. These cellular responses were mediated by the TfR1-internalization motif, YXXΦ. Therefore, pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. This study shed light on a new role of TfR1 as a signaling competent receptor. Targeting this pathway could provide alternative approaches to treat anemia, in particular in Epo hypo-responsive patients and dyserythropoiesis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.