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Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Coulon, Severine; Dussiot, Michael; Grapton, Damien; Maciel, Thiago Trovati; Wang, Pamella Huey Mei; Callens, Celine; Tiwari, Meetu Kaushik; Agarwal, Saurabh; Fricot, Aurelie and Vandekerckhove, Julie, et al. (2011) In Nature Medicine 17(11). p.163-1456
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... (More)
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, YXX Phi. 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. (Less)
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Nature Medicine
volume
17
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11
pages
163 - 1456
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Nature Publishing Group
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  • wos:000296779300037
  • scopus:81255135833
ISSN
1546-170X
DOI
10.1038/nm.2462
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English
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@article{5f7074f7-befb-41ee-97fe-86dd8943167b,
  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, YXX Phi. 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.},
  author       = {Coulon, Severine and Dussiot, Michael and Grapton, Damien and Maciel, Thiago Trovati and Wang, Pamella Huey Mei and Callens, Celine and Tiwari, Meetu Kaushik and Agarwal, Saurabh and Fricot, Aurelie and Vandekerckhove, Julie and Tamouza, Houda and Zermati, Yael and Ribeil, Jean-Antoine and Djedaini, Kamel and Oruc, Zeliha and Pascal, Virginie and Courtois, Genevieve and Arnulf, Bertrand and Alyanakian, Marie-Alexandra and Mayeux, Patrick and Leanderson, Tomas and Benhamou, Marc and Cogne, Michel and Monteiro, Renato C. and Hermine, Olivier and Moura, Ivan C.},
  issn         = {1546-170X},
  language     = {eng},
  number       = {11},
  pages        = {163--1456},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia},
  url          = {http://dx.doi.org/10.1038/nm.2462},
  volume       = {17},
  year         = {2011},
}