Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Abstract

Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.

Emerging EPO and EPO receptor regulators and signal transducers

“…Specifically, Tfr1 ligation by polymeric-IgA1 (p-IgA1) in murine erythroblasts increases EPO/EPOR-dependent mitogenactivated protein kinase and phosphatidylinositol 3-kinase signaling. 48 This occurs in the absence of transferrin binding, but depends upon a Tfr1 endocytic motif. In a knock-in model, human p-IgA1 enhances recovery from anemia due to 5-fluorouracil, hypoxia, and hemolytic anemia.…”

Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

“…Mechanisms underlying this response comprise modulation of erythropoietin signaling by transferrin receptors and by aconitase enzymes, which require iron to convert citrate to isocitrate (IC) (11)(12)(13). High levels of aconitase activity are specifically required for erythropoiesis such that in vitro enzymatic inhibition blunts cellular responsiveness to EPO and in vivo inhibition causes anemia (12,13).…”

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…[96][97][98][99] Similarly, stem cell factor (Scf) and its receptor, c-Kit, have an important role in the expansion of stress erythroid progenitors via Erk and Akt, which is enhanced by the concomitant activation of the glucocorticoid receptor (GR). 100 Additional factors that might contribute to SE are the RNA-binding protein ZFP36L2, 101 the Notch receptor 2, 102 the anti-inflammatory polymeric immunoglobulin A1 (pIgA1) 103 and dexamethasone. 104 In particular, dexamethasone, in addition to inducing proliferation of proerythroblasts, 105 stimulates expansion of these cells indirectly by supporting the activity of macrophages.…”