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Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN

Item Type:Article
Title:Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN
Creators Name:Schreiber, A., Luft, F.C. and Kettritz, R.
Abstract:ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1{beta} generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1{beta} levels compared with mice transplanted with wild-type bone marrow. IL-1{beta} receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1{beta} generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1{beta} generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1{beta} generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.
Keywords:ANCA, GN, NADPH Oxidase, Vasculitis, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:411-424
Date:February 2015
Official Publication:https://doi.org/10.1681/ASN.2013111177
PubMed:View item in PubMed

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