Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa.

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J.D. and I.N.-B. are joint first authors, and A.T., M.C.-A., M.B., S.L.E., E.H. and K.N. contributed equally to this work. We thank M. Ulvmar, E. Ross, G. Volpe, P. Cauchy and A. Cunningham for their advice, R. Bird and S. Kissane for their assistance with cell sorting and microarray experiments, respectively, H. Vyas and P. Kelay for help with laboratory work and D. Santovito for help with statistical analysis. We thank M. Mack (University of Regensburg) and M. Uchikawa (Japanese Red Cross) for their generous gifts of antibodies specific for mouse CCR2 and human ACKR1 antibody, respectively, and J. Allen (University of Manchester) and M. Bader (Max Delbruck Center) for critical reading of the manuscript and their suggestions. A.R. is grateful to M. Tsaloumas, A. Denniston and N. Glover for the vision. Supported by Medical Research Council grant G0802838 (A.R.), a Senior Visiting Fellowship of the Center for Advanced Studies LMU, Munich (A.R.), Wellcome Trust grant WT090962MA (I.N.-B., A.R. and P.M.), Deutsche Zentrum Für Herz-Kreislauf-Forschung 86X2600229 (J.D. and C.W.), a Marie Curie Actions Intra-European Fellowship ATHEROCHEMOKINE (J.D.), Deutsche Forschungsgemeinschaft grants SFB1123/A1 (C.W.), SFB1123/Z1 (M.B. and R.T.A.M.) and INST 409/150-1 FUG (C.W. and R.T.A.M.), European Research Council grant ERC AdG °692511 (C.W.), Swiss National Science Foundation Sinergia grant CRSII3_160719 (E.H. and A.R.), a TransCard PhD fellowship in Translational Cardiovascular and Metabolic Medicine of the Helmholtz International Research School (K.N.), an ERA-EDTA short-term fellowship (K.A.) and Ministry of Economy, Industry and Competitiveness (MINECO) grant AF2015-65607-R (A.H.). The CNIC is supported by MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award).

Author information

Author notes

    • Antal Rot

    Present address: William Harvey Research Institute, Queen Mary University of London, London, UK.

    • Johan Duchene
    •  & Igor Novitzky-Basso

    These authors contributed equally to this work.


  1. Institute for Cardiovascular Prevention, Ludwig-Maximilians University (LMU), Munich, Germany.

    • Johan Duchene
    • , Mariaelvy Bianchini
    • , Katrin Nitz
    • , Remco T A Megens
    • , Andres Hidalgo
    • , Christian Weber
    •  & Antal Rot
  2. Blood and Marrow Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK.

    • Igor Novitzky-Basso
  3. Department of Microbiology and Immunobiology and Center for Immune Imaging, Harvard Medical School, Boston, Massachusetts, USA.

    • Aude Thiriot
    •  & Ulrich H von Andrian
  4. Ragon Institute, Cambridge, Massachusetts, USA.

    • Aude Thiriot
    •  & Ulrich H von Andrian
  5. Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

    • Maria Casanova-Acebes
    •  & Andres Hidalgo
  6. Centre for Immunology and Infection, Department of Biology, University of York, Heslington, UK.

    • S Leah Etheridge
    • , Elin Hub
    • , Katharina Artinger
    •  & Antal Rot
  7. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

    • Katrin Nitz
  8. Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

    • Katharina Artinger
    •  & Kathrin Eller
  9. Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

    • Jorge Caamaño
    •  & Paul Moss
  10. Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.

    • Thomas Rülicke
  11. Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands.

    • Remco T A Megens
    •  & Christian Weber
  12. Center for Advanced Studies, Ludwig-Maximilians University, Munich, Germany.

    • Antal Rot


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A.R. conceived the study; J.D., I.N.-B., R.T.A.M., U.H.v.A., A.H., C.W. and A.R. designed the experiments; J.D., I.N.-B., A.T., M.C.-A., M.B., S.L.E., E.H., K.N., K.A. and T.R. performed the experiments and evaluated the data; J.D., I.N.-B., K.E., J.C., P.M., R.T.A.M., U.H.v.A., A.H., C.W. and A.R. interpreted the data; and A.R., J.D. and C.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christian Weber or Antal Rot.

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