Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis

Johan Duchene, Igor Novitzky-Basso, Aude Thiriot, Maria Casanova-Acebes, Mariaelvy Bianchini, S. Leah Etheridge, Elin Hub, Katrin Nitz, Katharina Artinger, Kathrin Eller, Jorge Caamaño, Thomas Rülicke, Paul Moss, Remco T.A. Megens, Ulrich H. Von Andrian, Andres Hidalgo, Christian Weber, Antal Rot

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)753-761
Number of pages9
JournalNature Immunology
Volume18
Issue number7
DOIs
StatePublished - 20 Jun 2017
Externally publishedYes

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