Centre National de la Recherche Scientifique (CNRS) Unité Mixte Recherche (UMR) 8147, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France.
Nat Med. 2011 Oct 23;17(11):1456-65. doi: 10.1038/nm.2462.
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.
由于促红细胞生成素（Epo）产生不足和/或对其反应不足而导致的贫血是慢性肾脏病和癌症的主要并发症。调节红细胞对 Epo 敏感性的机制仍知之甚少。我们表明，当在亚最佳浓度下与 Epo 一起培养时，转铁蛋白受体 1（TfR1）结合的多聚免疫球蛋白 A1（pIgA1）可挽救红细胞的生长和集落形成潜能。在生理条件下，与对照小鼠相比，表达人 IgA1 的小鼠中的红细胞数量增加。这些小鼠的低氧应激导致 pIgA1 和红细胞扩增增加。与人 IgA1 表达或用 TfR1 配体 pIgA1 或铁结合转铁蛋白（Fe-Tf）处理野生型小鼠可加速急性贫血的恢复。通过 pIgA1 或 Fe-Tf 与 TfR1 的结合，通过诱导有丝分裂原激活的蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）信号通路的激活，增加细胞对 Epo 的敏感性。这些细胞反应是通过 TfR1 内化基序 YXXΦ 介导的。我们的研究结果表明，pIgA1 和 TfR1 是生理和病理情况下红细胞生成的正调节剂。靶向该途径可能为治疗无效性红细胞生成和贫血提供替代方法。
