article · Journal of the American Society of Nephrology
Most individuals of West African ancestry carry a genetic variation in the ACKR1 gene that halts receptor expression on red blood cells while preserving it on endothelial cells. Using two genetically modified mouse models that selectively lack red blood cell ACKR1, investigators examined the receptor's role in immune-mediated kidney disease. Mice lacking erythroid ACKR1 showed worsened disease severity and renal fibrosis following the induction of nephrotoxic serum nephritis compared to controls. This heightened disease activity stemmed from shifts in the myeloid lineage, including altered blood chemokine levels, bone marrow monocytes exhibiting activated and migratory traits, and an influx of kidney-infiltrating macrophages with a profibrotic profile. Expression of ACKR1 within kidney vascular endothelial cells remained unaffected. The findings explain a direct mechanism by which erythroid ACKR1 deficiency exacerbates kidney injury.
A common genetic trait in populations of West African ancestry eliminates the ACKR1 receptor specifically from red blood cells. By revealing how this absence alters immune cells and promotes kidney fibrosis, this research provides vital biological insight into why certain populations may face more severe outcomes from inflammatory kidney diseases.
This is early-stage research in animal models that identifies specific immune mechanisms linking red blood cell genetics to kidney disease progression. It could eventually inform the development of targeted therapies or risk stratification tools for immune-mediated nephritis in specific patient populations, but the abstract does not indicate an immediate commercial application pathway or near-term product development.
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KEY POINTS: Selective erythroid atypical chemokine receptor 1 deficiency exacerbated disease activity in experimental GN via changes of the myeloid lineage. Activated monocytes and profibrogenic phenotypes of macrophages underlaid the kidney phenotype observed in erythroid-silent individuals. Genetically modified mouse models showed pathomechanisms of kidney diseases in patients of West African ancestry with erythroid atypical chemokine receptor 1 deficiency. BACKGROUND: Single-nucleotide polymorphisms of the atypical chemokine receptor 1 ( ACKR1 ) gene encode human Duffy antigen blood groups. Most 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 Duffy-negative transgene mice and chimeric wild-type 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 with their respective controls. Mice lacking erythroid ACKR1 exhibited altered serum chemokine levels and bone marrow monocytes displaying activated and promigratory 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 demonstrates that erythroid-specific ACKR1 deficiency led to an increased infiltration of the kidney by macrophages with an altered profibrotic phenotype in nephrotoxic serum nephritis, resulting in aggravated kidney disease.
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DOI: 10.1681/asn.0000000878
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