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.

[1]  M. Bissell.  Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies , 2009 .

[2]  D. Hourcade,et al.  The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis , 2008, Proceedings of the National Academy of Sciences.

[3]  V. Videm,et al.  Complement Activation by Neutrophil Granulocytes , 2008, Scandinavian journal of immunology.

[4]  C. Mackay,et al.  Functional roles for C5a receptors in sepsis , 2008, Nature Medicine.

[5]  C. McKerlie,et al.  C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a , 2007, Nature.

[6]  R. Falk,et al.  Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies. , 2006, Journal of the American Society of Nephrology : JASN.

[7]  M. Honda,et al.  Terminal complement complexes in childhood type I membranoproliferative glomerulonephritis. , 2006, Journal of nephrology.

[8]  M. Nangaku,et al.  Cellular and molecular biology of membranous nephropathy. , 2006, Journal of nephrology.

[9]  Pixu Liu,et al.  An Anti-inflammatory Function for the Complement Anaphylatoxin C5a-binding Protein, C5L2* , 2005, Journal of Biological Chemistry.

[10]  S. Nourshargh,et al.  Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. , 2005, Blood.

[11]  R. Quigg,et al.  Signaling through Up-Regulated C3a Receptor Is Key to the Development of Experimental Lupus Nephritis1 , 2005, The Journal of Immunology.

[12]  P. Heeringa,et al.  Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. , 2005, The American journal of pathology.

[13]  P. Heeringa,et al.  The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. , 2005, The American journal of pathology.

[14]  F. Luft,et al.  Membrane proteinase 3 expression and ANCA-induced neutrophil activation. , 2004, Kidney international.

[15]  M. Haas,et al.  Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. , 2004, Kidney international.

[16]  J. Krause,et al.  C5L2, a nonsignaling C5A binding protein. , 2003, Biochemistry.

[17]  J. Schifferli,et al.  Complement inhibition in renal diseases. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[18]  J. Younger,et al.  Generation of C5a by phagocytic cells. , 2002, The American journal of pathology.

[19]  P. Heeringa,et al.  Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. , 2002, The Journal of clinical investigation.

[20]  John D Lambris,et al.  Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. , 2002, Blood.

[21]  J. Klein,et al.  Phosphatidylinositol 3-kinase controls antineutrophil cytoplasmic antibodies-induced respiratory burst in human neutrophils. , 2002, Journal of the American Society of Nephrology : JASN.

[22]  A. Schmaier,et al.  Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. , 2002, The American journal of pathology.

[23]  B. Jaber,et al.  C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway. , 2002, Kidney international.

[24]  F. Luft,et al.  Role of mitogen-activated protein kinases in activation of human neutrophils by antineutrophil cytoplasmic antibodies. , 2001, Journal of the American Society of Nephrology : JASN.

[25]  R. Gans,et al.  Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. , 2000, Kidney international.

[26]  M. Enomoto,et al.  A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. , 2000, Molecular immunology.

[27]  N. Maeda,et al.  Severe Impairment in Early Host Defense againstCandida albicans in Mice Deficient in Myeloperoxidase , 1999, Infection and Immunity.

[28]  C. Alpers,et al.  Renal microvascular injury induced by antibody to glomerular endothelial cells is mediated by C5b-9. , 1997, Kidney international.

[29]  A. Maxwell,et al.  Up‐regulation of the granulocyte adhesion molecule Mac‐1 by autoantibodies in autoimmune vasculitis , 1997, Clinical and experimental immunology.

[30]  D. Adu,et al.  IL‐1β production by human polymorphonuclear leucocytes stimulated by anti‐neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis , 1996, Clinical and experimental immunology.

[31]  W. Vogt.  Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. , 1996, Immunobiology.

[32]  M. Oppermann,et al.  Detection of C5a receptors on human eosinophils and inhibition of eosinophil effector functions by anti‐C5a receptor (CD88) antibodies , 1996, European journal of immunology.

[33]  R. Falk,et al.  Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells. , 1995, Renal failure.

[34]  K. Tomooka,et al.  Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide‐related oxygen radicals produced by activated neutrophils , 1992, Clinical and experimental immunology.

[35]  W. Vogt,et al.  Activation of the fifth component of human complement by oxygen-derived free radicals, and by methionine oxidizing agents: a comparison. , 1992, Immunobiology.

[36]  C. Gerard,et al.  The chemotactic receptor for human C5a anaphylatoxin , 1991, Nature.

[37]  R J Falk,et al.  Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Perez,et al.  Chemotactic responses of human peripheral blood monocytes to the complement-derived peptides C5a and C5a des Arg. , 1985, Journal of immunology.

[39]  P. Naccache,et al.  The inhibition of neutrophil granule enzyme secretion and chemotaxis by pertussis toxin , 1985, The Journal of cell biology.

[40]  E. Pick,et al.  Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. , 1981, Journal of immunological methods.

[41]  I. Olsson,et al.  Cationic proteins of human granulocytes. VI. Effects on the complement system and mediation of chemotactic activity. , 1975, Journal of immunology.