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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Hereditary anemias of the mouse: a review for geneticists. Adv. Genet. 20, 357–459 (1979).

  2. 2.

    Erythropoietin and its mode of action. Blood Cells 10, 147–162 (1984).

  3. 3.

    et al. Caspase activation is required for terminal erythroid differentiation. J. Exp. Med. 193, 247–254 (2001).

  4. 4.

    et al. Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445, 102–105 (2007).

  5. 5.

    & Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248, 378–381 (1990).

  6. 6.

    et al. Survival or death of individual proerythroblasts results from differing erythropoietin sensitivities: a mechanism for controlled rates of erythrocyte production. Blood 82, 2340–2352 (1993).

  7. 7.

    , , , & Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396–399 (1999).

  8. 8.

    et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93, 111–123 (1998).

  9. 9.

    et al. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446, 92–96 (2007).

  10. 10.

    , , , & The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205–214 (2008).

  11. 11.

    et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J. Exp. Med. 194, 417–425 (2001).

  12. 12.

    et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J. Exp. Med. 205, 143–154 (2008).

  13. 13.

    & Mucosal immunoglobulins. Immunol. Rev. 206, 64–82 (2005).

  14. 14.

    & IgA Fc receptors. Annu. Rev. Immunol. 21, 177–204 (2003).

  15. 15.

    et al. A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood 103, 1838–1845 (2004).

  16. 16.

    , , , & Autoimmunity in IgA deficiency: revisiting the role of IgA as a silent housekeeper. J. Clin. Immunol. 28 (Suppl 1), S56–S61 (2008).

  17. 17.

    et al. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J. Am. Soc. Nephrol. 15, 622–634 (2004).

  18. 18.

    et al. Premature replacement of mu with alpha immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation. Proc. Natl. Acad. Sci. USA 107, 3064–3069 (2010).

  19. 19.

    et al. Joining chain-expressing and -nonexpressing B cell populations in the mouse. J. Exp. Med. 194, 557–570 (2001).

  20. 20.

    , & Selective transport of IgA. Cellular and molecular aspects. Gastroenterol. Clin. North Am. 20, 441–471 (1991).

  21. 21.

    et al. Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis. Blood 93, 796–803 (1999).

  22. 22.

    et al. Real-time monitoring of stress erythropoiesis in vivo using Gata1 and β-globin LCR luciferase transgenic mice. Blood 108, 726–733 (2006).

  23. 23.

    Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone. Exp. Hematol. 33, 1263–1270 (2005).

  24. 24.

    et al. The biology of stress erythropoiesis and erythropoietin production. Ann. N. Y. Acad. Sci. 718, 83–(1994).

  25. 25.

    Molecular insights into stress erythropoiesis. Curr. Opin. Hematol. 14, 215–224 (2007).

  26. 26.

    et al. High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia. J. Exp. Med. 190, 1689–1696 (1999).

  27. 27.

    , , & The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes. J. Exp. Med. 191, 2171–2182 (2000).

  28. 28.

    et al. Transferrin therapy ameliorates disease in β-thalassemic mice. Nat. Med. 16, 177–182 (2010).

  29. 29.

    et al. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J. Exp. Med. 207, 731–750 (2010).

  30. 30.

    et al. Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy. J. Am. Soc. Nephrol. 16, 2667–2676 (2005).

  31. 31.

    , & Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor. J. Biol. Chem. 267, 15970–15977 (1992).

  32. 32.

    , & A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. J. Biol. Chem. 267, 10866–10873 (1992).

  33. 33.

    et al. Identification of the erythropoietin receptor domain required for calcium channel activation. J. Biol. Chem. 274, 20465–20472 (1999).

  34. 34.

    et al. Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell 63, 1061–1072 (1990).

  35. 35.

    et al. TRPC3 activation by erythropoietin is modulated by TRPC6. J. Biol. Chem. 284, 4567–4581 (2009).

  36. 36.

    & Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104, 4287–4293 (2004).

  37. 37.

    , , , & Occupancy of the iron binding sites of human transferrin. Proc. Natl. Acad. Sci. USA 81, 4326–4330 (1984).

  38. 38.

    & The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta 1331, 1–40 (1997).

  39. 39.

    , & Transferrin-receptor–independent but iron-dependent proliferation of variant Chinese hamster ovary cells. Exp. Cell Res. 202, 326–336 (1992).

  40. 40.

    et al. Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis. Blood 111, 4375–4385 (2008).

  41. 41.

    , , , & Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells. Blood 102, 3147–3153 (2003).

  42. 42.

    & Co-operative signalling mechanisms required for erythroid precursor expansion in response to Epo and stem cell factor. Br. J. Haematol. 130, 121–129 (2005).

  43. 43.

    , & BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood 109, 4494–4502 (2007).

  44. 44.

    et al. Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis. J. Clin. Invest. 116, 683–694 (2006).

  45. 45.

    , , , & Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. J. Clin. Invest. 120, 4507–4519 (2010).

  46. 46.

    et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J. Clin. Oncol. 22, 1301–1307 (2004).

  47. 47.

    & Iron supplementation to treat anemia in patients with chronic kidney disease. Nat. Rev. Nephrol. 6, 699–710 (2010).

  48. 48.

    , & Evaluation of the iron status of a population. Blood 48, 449–455 (1976).

  49. 49.

    & The microcytic red cell and the anemia of inflammation. N. Engl. J. Med. 361, 1904–1906 (2009).

  50. 50.

    & Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 80, 1639–1647 (1992).

  51. 51.

    et al. Hemophagocytosis causes a consumptive anemia of inflammation. J. Exp. Med. 208, 1203–1214 (2011).

  52. 52.

    et al. Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM. Immunity 22, 31–42 (2005).

  53. 53.

    The structure and function of human IgA. Biochem. J. 271, 285–296 (1990).

  54. 54.

    et al. Operation Everest II: alterations in the immune system at high altitudes. J. Clin. Immunol. 8, 397–406 (1988).

  55. 55.

    et al. The glucocorticoid receptor is required for stress erythropoiesis. Genes Dev. 13, 2996–3002 (1999).

  56. 56.

    , , , & Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen. Blood 88, 75–81 (1996).

  57. 57.

    , & BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 105, 2741–2748 (2005).

  58. 58.

    et al. Hypoxia upregulates the synthesis of TGF-β 1 by human dermal fibroblasts. J. Invest. Dermatol. 97, 634–637 (1991).

  59. 59.

    et al. A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts. Immunity 30, 120–129 (2009).

  60. 60.

    et al. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood 108, 123–133 (2006).

Download references


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.


  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


  1. Search for Séverine Coulon in:

  2. Search for Michaël Dussiot in:

  3. Search for Damien Grapton in:

  4. Search for Thiago Trovati Maciel in:

  5. Search for Pamella Huey Mei Wang in:

  6. Search for Celine Callens in:

  7. Search for Meetu Kaushik Tiwari in:

  8. Search for Saurabh Agarwal in:

  9. Search for Aurelie Fricot in:

  10. Search for Julie Vandekerckhove in:

  11. Search for Houda Tamouza in:

  12. Search for Yael Zermati in:

  13. Search for Jean-Antoine Ribeil in:

  14. Search for Kamel Djedaini in:

  15. Search for Zeliha Oruc in:

  16. Search for Virginie Pascal in:

  17. Search for Geneviève Courtois in:

  18. Search for Bertrand Arnulf in:

  19. Search for Marie-Alexandra Alyanakian in:

  20. Search for Patrick Mayeux in:

  21. Search for Tomas Leanderson in:

  22. Search for Marc Benhamou in:

  23. Search for Michel Cogné in:

  24. Search for Renato C Monteiro in:

  25. Search for Olivier Hermine in:

  26. Search for Ivan C Moura in:


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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1 and 2 and Supplementary Methods

About this article

Publication history






Further reading