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.

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Acknowledgements

This work was supported by Agence Nationale pour la Recherche, Institut National contre le Cancer, cancéropôle d'Ile de France, Fondation pour la Recherche Médicale, Fondation de France, Association Laurette Fugain, Association pour la Recherche contre le Cancer, Société Française d'Hématologie, cent pour sang la vie, la Ligue contre le Cancer and INSERM/PNRNU2007 grants. S.C. is a recipient of Fondation pour la Recherche Médicale grant and a Société Française d'Hématologie grant. We would like to thank J. Kersual and S. Dauzet (CNRS UMR-S 8147) for experimental help and the Departments of Hematology, Obstetrics and Otorhinolaryngology at the Necker Hospital (Paris, France) for providing blood samples, cord blood samples and tonsil samples, respectively. We would like to thank J.L. Danan (CNRS FRE 3210), M. Heinis (INSERM U845), B. Ruiz (INSERM U780) (located at Paris Descartes University, Paris, France) and C. Clerici (INSERM U773, Bichat Hospital, Paris, France) for providing the hypoxia chambers and L.-J. Couderc at the Foch Hospital (Suresnes, France) for providing blood samples. We are especially thankful to S. Izui (Department of Pathology and Immunology, University Medical Center, Geneva, Switzerland) for providing the 34-3C IgG2a monoclonal antibody and for fruitful discussions.

Author information

Author notes

    • Séverine Coulon
    •  & Jean-Antoine Ribeil

    Present addresses: Service de Pharmacie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France (S.C.) and Departement de Biothérapie, Hôpital Necker, Paris, France (J.-A.R.).

    • Séverine Coulon
    •  & Michaël Dussiot

    These authors contributed equally to this work.

Affiliations

  1. Centre National de la Recherche Scientifique (CNRS) Unité Mixte Recherche (UMR) 8147, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France.

    • Séverine Coulon
    • , Michaël Dussiot
    • , Damien Grapton
    • , Celine Callens
    • , Aurelie Fricot
    • , Julie Vandekerckhove
    • , Yael Zermati
    • , Jean-Antoine Ribeil
    • , Geneviève Courtois
    •  & Olivier Hermine
  2. Institut National de la Santé et de la Recherche Médicale (INSERM) U699, Paris, France.

    • Michaël Dussiot
    • , Damien Grapton
    • , Thiago Trovati Maciel
    • , Pamella Huey Mei Wang
    • , Meetu Kaushik Tiwari
    • , Saurabh Agarwal
    • , Houda Tamouza
    • , Marc Benhamou
    • , Renato C Monteiro
    •  & Ivan C Moura
  3. Faculté de Médecine and Université Denis Diderot Paris VII, Paris, France.

    • Michaël Dussiot
    • , Damien Grapton
    • , Thiago Trovati Maciel
    • , Pamella Huey Mei Wang
    • , Meetu Kaushik Tiwari
    • , Saurabh Agarwal
    • , Houda Tamouza
    • , Marc Benhamou
    • , Renato C Monteiro
    •  & Ivan C Moura
  4. Clinique Geoffroy Saint-Hilaire, Paris, France.

    • Kamel Djedaini
  5. Université de Limoges, CNRS UMR 6101, Limoges, France.

    • Zeliha Oruc
    • , Virginie Pascal
    •  & Michel Cogné
  6. Service d'Immuno-Hématologie, Faculté de Médecine and Université Denis Diderot Paris VII, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Paris, France.

    • Bertrand Arnulf
  7. Laboratoire EA3963, Faculté de Médecine and Université Denis Diderot Paris VII, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Paris, France.

    • Bertrand Arnulf
  8. INSERM U1013, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France.

    • Marie-Alexandra Alyanakian
  9. Laboratoire d'Immunologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.

    • Marie-Alexandra Alyanakian
  10. Institut Cochin, Département d'Hématologie, Paris, France.

    • Patrick Mayeux
  11. INSERM U567, Paris, France.

    • Patrick Mayeux
  12. CNRS UMR 8104, Université Paris Descartes, Faculté de Médecine, Paris, France.

    • Patrick Mayeux
  13. Immunology Group, Lund University, Lund, Sweden.

    • Tomas Leanderson
  14. Service d'Hématologie clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.

    • Olivier Hermine

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Contributions

S.C., M.D. and D.G. designed and performed all experiments, analyzed the data and helped write the manuscript. T.T.M. performed calcium experiments, analyzed the data and helped write the manuscript. P.H.M.W., C.C., A.F., J.V., H.T., Y.Z. and G.C. performed experiments and analyzed the data. M.K.T. planned, designed and constructed the TfR1 mutants and helped to write the manuscript. S.A. performed molecular biology experiments. J.-A.R., K.D., Z.O., V.P., B.A., M.-A.A., T.L. and M.C. provided human samples and mice. P.M. contributed to writing the manuscript and provided helpful discussions. M.B. provided helpful discussions and crucial analysis of the data and wrote the manuscript. R.C.M. supervised the project, analyzed the data and wrote the manuscript. O.H. designed the study, supervised the overall project, analyzed the data and wrote the manuscript. I.C.M. designed the study, supervised the overall project, performed experiments, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Renato C Monteiro or Olivier Hermine or Ivan C Moura.

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DOI

https://doi.org/10.1038/nm.2462

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