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Abstract: FR-PO579

CC Chemokine Receptor 2 (CCR2) in ANCA Disease: Different Roles in Glomerulonephritis vs. Lung Granulomatosis in MPO-ANCA Induced Mouse Model

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Hu, Peiqi, University of North Carolina, Chapel Hill, North Carolina, United States
  • Xiao, Hong, University of North Carolina, Chapel Hill, North Carolina, United States
  • Alba, Marco A., University of North Carolina, Chapel Hill, North Carolina, United States
  • Gou, Shen-Ju, University of North Carolina, Chapel Hill, North Carolina, United States
  • Hu, Yanglin, University of North Carolina, Chapel Hill, North Carolina, United States
  • Falk, Ronald, University of North Carolina, Chapel Hill, North Carolina, United States
  • Jennette, J. Charles, University of North Carolina, Chapel Hill, North Carolina, United States
Background

Antineutrophil cytoplasmic autoantibody disease has a spectrum of necrotizing small vessel vasculitis, including necrotizing crescentic glomerulonephritis (NCGN) and lung granulomatosis (LG). Neutrophils and monocytes/macrophages are key players in the pathogenesis of ANCA disease. CC chemokine receptor 2 (CCR2) serves as the main receptor for CCL2, and modulates recruitment of monocytes/macrophages and neutrophils to sites of inflammation. CCR2 has dual pro-inflammatory and anti-inflammatory roles in inflammation. The aim of the present study was to elucidate the role of CCR2 in the pathogenesis of NCGN and LG in an animal model of MPO-ANCA disease

Methods

A murine MPO-ANCA induced model was used to evaluate the in vivo role of CCR2 in ANCA GN and LG. CCR2-/- and B6 WT mice were treated with a single dose of anti-MPO IgG iv at day 0; or a dose of intratracheal LPS administration at day 0 plus two consecutive doses of anti-MPO IgG on day 0 and day1. Mice were sacrificed at day7 and kidneys and lungs collected for pathologic assessment.

Results

On day 7 after receiving a single dose of MPO-ANCA IgG, WT mice (n=8) had 13.9% mean crescents (crescent between arrows in Figure 1), whereas CCR2-/- mice (n=3) had less GN with 0.5% crescents. However, WT mice had no LG, whereas CCR2-/- mice had well defined LG often with a central core of neutrophils surrounded by macrophages (between arrows in Figure 2).

Conclusion

Our preliminary data indicate that CCR2 deficiency reduces the severity of necrotizing inflammation in glomeruli, whereas CCR2 deficiency facilitates granulomatous disease in lungs. Insights into the role of CCR2 in the pathogenesis of ANCA disease will help guide development of safe and effective therapies involving CCR2 and CCR2 ligand modulation for ANCA disease.

Funding

  • NIDDK Support