Erythroid ACKR1 Deficiency Aggravates Immune-Mediated Kidney Disease.

BACKGROUND Single nucleotide polymorphisms of the atypical chemokine receptor 1 (ACKR1) gene encode human Duffy Antigen blood groups. The majority of individuals of West African ancestry carry a single nucleotide polymorphism in the promoter region of the ACKR1 gene that disrupts its transcription in erythroid cells but not in venular endothelial cells, leading to an "erythroid-silent", FyBES Duffy phenotype. METHODS We used two mouse models of erythroid-selective ACKR1 deficiency to delineate the fundamental role of this receptor in the erythroid compartment in regulating the development of experimental immune-mediated kidney disease. RESULTS Humanized transgenic Duffy erythroid-silent FyBESTG mice and chimeric WT mice transplanted with ACKR1-deficient bone marrow, both selectively lacking erythroid ACKR1, showed increased disease activity and fibrosis after induction of nephrotoxic serum nephritis, as compared to their respective controls. Mice lacking erythroid ACKR1 exhibited altered serum chemokine levels and bone marrow monocytes displaying activated and pro-migratory phenotypes. Moreover, they showed an increase in kidney infiltrating macrophages that were characterized by a profibrotic transcriptome signature. No changes in ACKR1 expression in kidney vascular endothelial cells were seen in erythroid ACKR1-deficient mice with or without nephrotoxic serum nephritis. CONCLUSIONS Our data suggest that erythroid-specific ACKR1 deficiency leads to an increased infiltration of the kidney by macrophages with an altered profibrotic phenotype in nephrotoxic serum nephritis, resulting in aggravated kidney disease.