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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.
AuthorsAdrian Schreiber, Friedrich C Luft, Ralph Kettritz
JournalJournal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 26 Issue 2 Pg. 411-24 (Feb 2015) ISSN: 1533-3450 [Electronic] United States
PMID25012177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 by the American Society of Nephrology.
Chemical References
  • Antibodies, Antineutrophil Cytoplasmic
  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Pirb protein, mouse
  • Reactive Oxygen Species
  • Receptors, Immunologic
  • Superoxides
  • Peroxidase
  • NADPH Oxidase
  • neutrophil cytosolic factor 1
  • Caspase 1
Topics
  • Animals
  • Antibodies, Antineutrophil Cytoplasmic (adverse effects)
  • Caspase 1 (metabolism)
  • Cells, Cultured
  • Disease Models, Animal
  • Glomerulonephritis (chemically induced, metabolism, physiopathology)
  • Humans
  • In Vitro Techniques
  • Inflammasomes (physiology)
  • Interleukin 1 Receptor Antagonist Protein (pharmacology)
  • Interleukin-1beta (metabolism)
  • Kidney (drug effects, metabolism, pathology)
  • Mice
  • Mice, Knockout
  • NADPH Oxidase (deficiency, genetics, metabolism, physiology)
  • Peroxidase (metabolism)
  • Phagocytes (enzymology, pathology)
  • Reactive Oxygen Species (metabolism)
  • Receptors, Immunologic (deficiency, genetics, metabolism)
  • Superoxides (metabolism)

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