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Neutrophil serine proteases promote IL-1beta generation and injury in necrotizing crescentic glomerulonephritis

Item Type:Article
Title:Neutrophil serine proteases promote IL-1beta generation and injury in necrotizing crescentic glomerulonephritis
Creators Name:Schreiber, A. and Pham, C.T. and Hu, Y. and Schneider, W. and Luft, F.C. and Kettritz, R.
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-1beta than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1beta in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1beta was NSP dependent; exogenous addition of PR3 restored IL-beta 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-1beta is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1beta generation and that these processes may provide therapeutic targets for ANCA-mediated diseases in humans.
Keywords:Animal Disease Models, Anti-Idiotypic Antibodies, Antineutrophil Cytoplasmic Antibodies, Bone Marrow Transplantation, Cathepsin C, Cell Movement, Glomerulonephritis, Inbred C57BL Mice, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Interleukin-1 Receptors, Kidney, Kidney Cortex Necrosis, Knockout Mice, Monocytes, Neutrophils, Peroxidase, Serine Proteases, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:470-482
Date:March 2012
Official Publication:https://doi.org/10.1681/ASN.2010080892
PubMed:View item in PubMed

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