title: Neutrophil serine proteases promote IL-1β generation and injury in necrotizing crescentic glomerulonephritis.
abstract: The pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic GN (NCGN) is incompletely understood. Dipeptidyl peptidase I (DPPI) is a cysteine protease required for the activation of neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase, and proteinase 3, which are enzymes that modulate inflammation. We used a mouse model of anti-myeloperoxidase (MPO) antibody-induced NCGN to determine whether active NSPs contribute to its pathogenesis. MPO-deficient animals immunized with murine MPO, irradiated, and transplanted with wild-type bone marrow developed NCGN. In contrast, transplantation with bone marrow that lacked DPPI or lacked both neutrophil elastase and proteinase 3 protected mice from NCGN induced by anti-MPO antibody. The kidneys of mice reconstituted with DPPI-deficient bone marrow generated significantly less IL-1β than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1β in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1β was NSP dependent; exogenous addition of PR3 restored IL-β production in DPPI-deficient monocytes. Last, the IL-1 receptor antagonist anakinra protected animals against anti-MPO antibody-induced NCGN (16.7%±6.0% versus 2.4%±1.7% crescents), suggesting that IL-1β is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1β generation and that these processes may provide therapeutic targets for ANCA-mediated diseases in humans.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Charité Berlin, Berlin, Germany. adrian.schreiber@charite.de
authors.forename: Adrian
authors.initials: A
authors.lastname: Schreiber
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schneider
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Ralph
authors.initials: R
authors.lastname: Kettritz
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000009:adverse effects; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000009:adverse effects; D016026:Bone Marrow Transplantation; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007673:Kidney Cortex Necrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D009195:Peroxidase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000187:drug effects; D057057:Serine Proteases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019268:Antibodies, Antineutrophil Cytoplasmic; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D009195:Peroxidase; D057057:Serine Proteases; D020789:Cathepsin C; C533919:Ctsc protein, mouse