Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN.

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.

[1]  U. Panzer,et al.  Leukocyte-derived MMP9 is crucial for the recruitment of proinflammatory macrophages in experimental glomerulonephritis. , 2013, Kidney international.

[2]  M. Hickey,et al.  Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus , 2012, Nature Medicine.

[3]  M. Shlomchik,et al.  NADPH Oxidase Inhibits the Pathogenesis of Systemic Lupus Erythematosus , 2012, Science Translational Medicine.

[4]  R. Kettritz.  How anti‐neutrophil cytoplasmic autoantibodies activate neutrophils , 2012, Clinical and experimental immunology.

[5]  Yeon-Ah Lee,et al.  Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes , 2012, Experimental & Molecular Medicine.

[6]  F. Luft,et al.  Neutrophil serine proteases promote IL-1β generation and injury in necrotizing crescentic glomerulonephritis. , 2012, Journal of the American Society of Nephrology : JASN.

[7]  A. Knox,et al.  Ciclesonide inhibits TNFα- and IL-1β-induced monocyte chemotactic protein-1 (MCP-1/CCL2) secretion from human airway smooth muscle cells , 2012, American journal of physiology. Lung cellular and molecular physiology.

[8]  C. Alpers,et al.  Anti-Proteinase 3 Anti-Neutrophil Cytoplasm Autoantibodies Recapitulate Systemic Vasculitis in Mice with a Humanized Immune System , 2012, PloS one.

[9]  Don L. Armstrong,et al.  Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase , 2011, Proceedings of the National Academy of Sciences.

[10]  Judy H. Cho,et al.  NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 , 2011, Gut.

[11]  P. Narasimhan,et al.  NADPH oxidase is involved in post-ischemic brain inflammation , 2011, Neurobiology of Disease.

[12]  A. Fischer,et al.  Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease. , 2010, Blood.

[13]  R. Holmdahl,et al.  Mice Producing Less Reactive Oxygen Species Are Relatively Resistant to Collagen Glycopeptide Vaccination against Arthritis , 2010, The Journal of Immunology.

[14]  D. Harrison,et al.  Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling. , 2010, American journal of physiology. Heart and circulatory physiology.

[15]  T. K. van den Berg,et al.  Human NLRP3 inflammasome activation is Nox1-4 independent. , 2010, Blood.

[16]  Y. Iwakura,et al.  Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis. , 2010, Journal of the American Society of Nephrology : JASN.

[17]  I. Cuthill,et al.  Reporting : The ARRIVE Guidelines for Reporting Animal Research , 2010 .

[18]  M. Sporn,et al.  NADPH Oxidase Limits Innate Immune Responses in the Lungs in Mice , 2010, PloS one.

[19]  J. Tschopp,et al.  Thioredoxin-interacting protein links oxidative stress to inflammasome activation , 2010, Nature Immunology.

[20]  S. Smeekens,et al.  Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease , 2010, Proceedings of the National Academy of Sciences.

[21]  Carl Nathan,et al.  Nonresolving Inflammation , 2010, Cell.

[22]  A. Sarin,et al.  Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis , 2009, The Journal of experimental medicine.

[23]  Masayuki Yamamoto,et al.  Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice1 , 2009, The Journal of Immunology.

[24]  Z. Werb,et al.  Netting neutrophils in autoimmune small-vessel vasculitis , 2009, Nature Medicine.

[25]  F. Luft,et al.  C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. , 2009, Journal of the American Society of Nephrology : JASN.

[26]  M. Turner,et al.  Chronic granulomatous disease as a risk factor for autoimmune disease. , 2008, The Journal of allergy and clinical immunology.

[27]  Minoru Fukuda,et al.  Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis , 2008, Nature Medicine.

[28]  F. Meissner,et al.  Superoxide dismutase 1 regulates caspase-1 and endotoxic shock , 2008, Nature Immunology.

[29]  J. Tschopp,et al.  Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica , 2008, Science.

[30]  W. Nauseef.  Nox enzymes in immune cells , 2008, Seminars in Immunopathology.

[31]  U. Grohmann,et al.  Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease , 2008, Nature.

[32]  R. Holmdahl,et al.  Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. , 2007, The Journal of clinical investigation.

[33]  L. Alfredsson,et al.  A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity , 2007, Arthritis research & therapy.

[34]  Y. Ikeda,et al.  Inactivation of cysteine and serine proteases by singlet oxygen. , 2007, Archives of biochemistry and biophysics.

[35]  R. Falk,et al.  Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies. , 2006, Journal of the American Society of Nephrology : JASN.

[36]  C. Savage,et al.  Mediation of endothelial cell damage by serine proteases, but not superoxide, released from antineutrophil cytoplasmic antibody-stimulated neutrophils. , 2006, Arthritis and rheumatism.

[37]  S. Nourshargh,et al.  Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis. , 2005, Journal of the American Society of Nephrology : JASN.

[38]  P. Heeringa,et al.  Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. , 2005, The American journal of pathology.

[39]  T. Hirche,et al.  Myeloperoxidase Plays Critical Roles in Killing Klebsiella pneumoniae and Inactivating Neutrophil Elastase: Effects on Host Defense1 , 2005, The Journal of Immunology.

[40]  L. Ellis,et al.  Interleukin-1β stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells , 2004, Oncogene.

[41]  L. Ellis,et al.  Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. , 2004, Oncogene.

[42]  M. Evans,et al.  Oxidative DNA damage: mechanisms, mutation, and disease , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  Jens Holmberg,et al.  Positional identification of Ncf1 as a gene that regulates arthritis severity in rats , 2003, Nature Genetics.

[44]  P. Galle,et al.  Kinetics of thrombomodulin release and endothelial cell injury by neutrophil‐derived proteases and oxygen radicals , 2002, Immunology.

[45]  P. Heeringa,et al.  Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. , 2002, The Journal of clinical investigation.

[46]  Richard B. Johnston,et al.  Chronic Granulomatous Disease: Report on a National Registry of 368 Patients , 2000, Medicine.

[47]  M. Dinauer,et al.  Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to Aspergillus fumigatus , 1997, The Journal of experimental medicine.

[48]  R J Falk,et al.  Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[49]  R. Dean,et al.  Free radicals inactivate human neutrophil elastase and its inhibitors with comparable efficiency. , 1989, Biochemical and biophysical research communications.

[50]  R. Falk,et al.  Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. , 1988, The New England journal of medicine.

[51]  E. Chi,et al.  New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. , 1987, The Journal of clinical investigation.

[52]  D. Stroncek,et al.  Neutrophil Oxidants Inactivate Alpha4 ‐Protease Inhibitor and Promote PMN‐Mediated Detachment of Cultured Endothelium: Protection by Free Methionine , 1986, Arteriosclerosis.

[53]  W. Gross,et al.  ANTICYTOPLASMIC ANTIBODIES IN WEGENER'S GRANULOMATOSIS , 1986, The Lancet.