title: Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN.
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-1β 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-1β levels compared with mice transplanted with wild-type bone marrow. IL-1β receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1β generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1β generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1β 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.
authors.affiliation: Experimental and Clinical Research Center at the Max-Delbrueck-Centrum Berlin and Campus Virchow Clinic, Medical Faculty of the Charité, Department of Nephrology and Intensive Care Medicine, Charité Berlin, Berlin, Germany adrian.schreiber@charite.de.
authors.forename: Adrian
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: Experimental and Clinical Research Center at the Max-Delbrueck-Centrum Berlin and.
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: Experimental and Clinical Research Center at the Max-Delbrueck-Centrum Berlin and Campus Virchow Clinic, Medical Faculty of the Charité, Department of Nephrology and Intensive Care Medicine, Charité Berlin, Berlin, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Kettritz
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000009:adverse effects*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D058847:Inflammasomes / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D010586:Phagocytes / Q000201:enzymology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C105949:Pirb protein, mouse; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D013481:Superoxides; D009195:Peroxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020170:Caspase 1
keywords: ANCA; GN; NADPH oxidase; vasculitis