Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis

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 erythroid cell expression of ACKR1, causing Duffy-negative phenotype. Here we describe an unexpected fundamental role that ACKR1 plays in hematopoiesis and provide the mechanism linking its absence with neutropenia. Nucleated erythroid cells highly expressed ACKR1, which facilitated their direct contacts with the hematopoietic stem cells. The absence of erythroid ACKR1 altered murine hematopoiesis, including stem and progenitor cells, ultimately giving rise to phenotypically distinct neutrophils, which readily left the circulation, causing neutropenia. Duffy-negative individuals developed a distinct profile of neutrophil effector molecules closely reflecting that 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 providing major implications for the selection advantages that have resulted in the paramount fixation of the rs2814778(G) polymorphism in Africa.