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Abstract: TH-OR059

Classical Monocytes Promote Crescent Formation and Necrosis in ANCA-Associated Necrotizing Crescentic Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Rousselle, Anthony, ECRC, Berlin, Germany
  • Kettritz, Ralph, ECRC, Berlin, Germany
  • Schreiber, Adrian, ECRC, Berlin, Germany
Background

The binding of circulating antineutrophil cytoplasmic autoantibodies (ANCAs) to neutrophils and monocytes and their subsequent activation are key events in the development of ANCA-associated vasculitis (AAV) and necrotizing crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the exact role of monocytes remains poorly described. Murine monocytes are classified into two functionally different subsets: Ly6Chi CCR2+ classical (inflammatory) monocytes (CM) and Ly6Clo CCR2- non-classical (patrolling) monocytes (NCM). Differentiation of circulating Ly6Chi monocytes into Ly6Clo monocytes is controlled by the transcription factor C/EBPβ. We showed recently that global monocyte depletion protected from ANCA-induced necrotizing crescentic glomerulonephritis (NCGN) in vivo. We now studied the exact contribution of the two distinct monocyte subsets in AAV.

Methods

To assess the role of both monocyte subsets in vivo, we used our AAV murine model: MPO-/- mice were immunized with murine MPO, sublethally irradiated and subsequently transplanted with hematopoietic cells from either WT, CCR2-/- , C/EBPβ+/+ or C/EBPβ-/- mice (all MPO positive). CCR2-/- mice had a reduction of circulating Ly6Chi monocytes whereas C/EBPβ-/- mice lacked circulating Ly6Clo monocytes. Mice were sacrificed and analyzed 8 weeks following transplantation. Urine was analyzed by dipstick, albuminuria by ELISA, glomerular necrosis and crescents by histology, and circulating and renal cell influx by flow cytometry.

Results

Blood composition confirmed the expected engraftment as CM and NCM were indeed significantly decreased in CCR2-/- and C/EBPβ-/- chimeric mice, respectively. WT, C/EBPβ+/+ and C/EBPβ-/- chimeric mice developed urine abnormalities and glomerular necrosis and crescent formation. In contrast, CCR2-/- chimeric mice did neither develop erythrocyturia and albuminuria nor NCGN. Flow cytometry showed significantly reduced renal infiltration of CM CCR2-/-. In contrast, renal neutrophil, macrophage and dendritic cell infiltration remained similar in all groups.

Conclusion

Our findings provide novel experimental evidence that classical monocytes are important contributors of kidney damage in ANCA-mediated NCGN. The exact molecular mechanisms by which classical monocytes promote kidney damage remains to be clarified.

Funding

  • Government Support - Non-U.S.