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Abstract: TH-PO026

Erythroid ACKR1 Expression Has Profound Impact on the Development of Experimental Glomerulonephritis

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Artinger, Katharina, Medical University of Graz, Graz, Austria
  • Novitzky-Basso, Igor, Queen Elizabeth University Hospital, Glasgow, United Kingdom
  • Kirsch, Alexander H., Medical University of Graz, Graz, Austria
  • Schabhüttl, Corina, Medical University of Graz, Graz, Austria
  • Hub, Elin, University of York, York, United Kingdom
  • Etheridge, Leah, University of York, York, United Kingdom
  • Eller, Philipp, Medical University of Graz, Graz, Austria
  • Rosenkranz, Alexander R., Medical University of Graz, Graz, Austria
  • Rot, Antal, University of York, York, United Kingdom
  • Eller, Kathrin, Medical University of Graz, Graz, Austria
Background

The majority of individuals of West African ancestry carry a polymorphic “erythroid silent” FyB(ES) variant of ACKR1. Individuals with FyB(ES) express ACKR1 on endothelial cells but not on erythroid cells. The FyB(ES) polymorphism is of special interest for understanding human kidney disease as the individuals of West African ancestry have higher incidence of chronic kidney diseases. Moreover, chemokine ligands of ACKR1 are involved in driving the inflammatory pathology in the experimental model of nephrotoxic serum nephritis (NTS).

Methods

We developed humanized transgenic mouse strains, which do not express mouse ACKR1 but instead either West African FyB(ES) or Caucasian FyB polymorphic ACKR1 variants. These strains as well as ACKR1-deficient and WT mice were subjected to NTS, a murine model of immune complex glomerulonephritis. The parameters of immunepathogenesis and kidney phenotype were evaluated after 14 days.

Results

Albuminuria, PAS and tubular injury scores were significantly increased in FyB(ES)tg and ACKR1-deficient mice as compared to their respective control strains. While monocytes were unchanged in peripheral blood, we found significantly increased numbers of macrophages and neutrophils infiltrating the kidneys of FyB(ES)tg and ACKR1-deficient mice. Interestingly, T cell numbers in the draining lymph nodes were comparable between FyB(ES)tg and ACKR1-deficient mice and their respective controls.

Conclusion

We found that NTS was more severe in ACKR1-deficient and FyB(ES) mice as compared to their respective controls. Our results show that ACKR1 expression in the erythroid compartment has a significant impact on the development of kidney disease. These findings have important implications for the pathomechanisms of glomerulonephritis in individuals of West African ancestry who lack ACKR1 selectively in the erythroid lineage.