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Abstract: PO2451

Complement C5a Receptor in Macrophage-Mediated Renal Inflammation and Fibrosis in Lupus Nephritis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Li, Chris, ChemoCentryx Inc, San Carlos, California, United States
  • Zhao, Bin N., ChemoCentryx Inc, San Carlos, California, United States
  • Dunlap, Carolyn, ChemoCentryx Inc, San Carlos, California, United States
  • Ertl, Linda, ChemoCentryx Inc, San Carlos, California, United States
  • Miao, Zhenhua, ChemoCentryx Inc, San Carlos, California, United States
  • Charo, Israel, ChemoCentryx Inc, San Carlos, California, United States
  • Sullivan, Kathleen M., ChemoCentryx Inc, San Carlos, California, United States
  • Schall, Thomas J., ChemoCentryx Inc, San Carlos, California, United States
Background

Lupus nephritis (LN) is caused by autoimmune responses and is a significant driver of end-stage renal disease in systemic lupus erythematosus patients. Complement activation, pro-inflammatory cytokine production, and the influx of macrophages have all been implicated in LN pathogenesis. The anaphylatoxin complement 5a (C5a) receptor 1 (C5aR) is a major driver of the pro-inflammatory functions of complement activation. We examined C5aR’s expression in kidney in lupus nephritis and investigated its role in controlling pro-fibrotic functions of macrophages.

Methods

C5aR expression, infiltrating immune cells, and fibrosis were examined by immunohistochemistry in LN patient kidney biopsies. M1 and M2 macrophages derived from human peripheral blood monocytes were used in in vitro assays to examine the effect of C5a stimulation and avacopan, a specific C5aR inhibitor, on the secretion of cytokines and other factors.

Results

In LN kidney biopsies, large numbers of macrophages, identified by CD68 staining, were observed in areas with severe fibrosis, and expressed C5aR. In addition, C5aR was detected on distal tubules in biopsies of both normal and lupus nephritis kidneys. C5a increased the production of inflammatory cytokines TNFa and IL-6 from both M1 and M2 macrophages in vitro. Chemokines (MCP-3, MIP-1a, MIP-1b and MIP-3a), matrix metalloproteinases (MMP3 and MMP8), and pro-fibrotic growth factors (fibroblast activation protein, platelet-derived growth factor-AA) were strongly increased in M2 macrophages with C5a stimulation, and these increases were blocked by the C5aR inhibitor avacopan.

Conclusion

C5aR activation induced macrophage secretion of factors that are known to drive inflammation, fibroblast activation and tissue fibrosis, and thus may contribute to LN disease progression. Inhibiting C5aR activity with avacopan blocks these pathological changes, and may provide therapeutic benefit to LN patients.