C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.
Anti-neutrophil cytoplasmic autoantibody (ANCA)-induced necrotizing crescentic glomerulonephritis (NCGN) requires complement participation in its pathogenesis. We tested the hypothesis that the anaphylatoxin C5a is pivotal to disease induction via the neutrophil C5a receptor (C5aR). Supernatants from ANCA-activated neutrophils activated the complement cascade in normal serum, producing C5a. This conditioned serum primed neutrophils for ANCA-induced respiratory burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade did not. Furthermore, recombinant C5a but not C3a dosage-dependently primed neutrophils for ANCA-induced respiratory burst. To test the role of C5aR in a model of NCGN, we immunized myeloperoxidase-deficient mice with myeloperoxidase, irradiated them, and transplanted bone marrow from wild-type mice or C5aR-deficient mice into them. All mice that received wild-type marrow (six of six) but only one of eight mice that received C5aR-deficient marrow developed NCGN (P < 0.05). Albuminuria and neutrophil influx into glomeruli were also significantly attenuated in the mice that received C5aR-deficient marrow (P < 0.05). In summary, C5a and the neutrophil C5aR may compose an amplification loop for ANCA-mediated neutrophil activation. The C5aR may provide a new therapeutic target for ANCA-induced necrotizing crescentic glomerulonephritis.
Schreiber
Adrian
A
Medical Faculty of the Charité, Department of Nephrology and Hypertension, Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, HELIOS-Klinikum-Berlin, Berlin, Germany. adrian.schreiber@gmx.de
Xiao
Hong
H
Jennette
J Charles
JC
Schneider
Wolfgang
W
Luft
Friedrich C
FC
Kettritz
Ralph
R
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism*; D001323:Autoantibodies / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D015926:Complement C3a / Q000737:chemistry; D015936:Complement C5a / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000737:chemistry* / Q000378:metabolism; D016897:Respiratory Burst; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D015926:Complement C3a; D015936:Complement C5a; D009195:Peroxidase