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 | Adrian Schreiber, Friedrich C Luft, Ralph Kettritz |
Journal | Journal 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 |
PMID | 25012177
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 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 Oxidases
- 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 Oxidases
(deficiency, genetics, metabolism, physiology)
- Peroxidase
(metabolism)
- Phagocytes
(enzymology, pathology)
- Reactive Oxygen Species
(metabolism)
- Receptors, Immunologic
(deficiency, genetics, metabolism)
- Superoxides
(metabolism)
|