Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Research output: Contribution to journalArticle

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.

Details

Authors
  • Severine Coulon
  • Michael Dussiot
  • Damien Grapton
  • Thiago Trovati Maciel
  • Pamella Huey Mei Wang
  • Celine Callens
  • Meetu Kaushik Tiwari
  • Saurabh Agarwal
  • Aurelie Fricot
  • Julie Vandekerckhove
  • Houda Tamouza
  • Yael Zermati
  • Jean-Antoine Ribeil
  • Kamel Djedaini
  • Zeliha Oruc
  • Virginie Pascal
  • Genevieve Courtois
  • Bertrand Arnulf
  • Marie-Alexandra Alyanakian
  • Patrick Mayeux
  • Marc Benhamou
  • Michel Cogne
  • Renato C. Monteiro
  • Olivier Hermine
  • Ivan C. Moura
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)1456-U163
JournalNature Medicine
Volume17
Issue number11
StatePublished - 2011
Peer-reviewedYes