Mediation of endothelial cell damage by serine proteases, but not superoxide, released from antineutrophil cytoplasmic antibody–stimulated neutrophils

Lü, Xiaomei; Garfield, Alastair S.; Rainger, G. Ed; Savage, Caroline O.S.; Nash, Gerard B.

doi:10.1002/art.21773

Cited by 46 publications

(32 citation statements)

References 28 publications

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“…Numerous in vitro studies established an ANCA-mediated robust Phox-dependent respiratory burst in neutrophils and although less well studied, monocytes. 2,[11][12][13][14]38,39 Together with the fact that ROS modify and damage proteins and lipids, ANCA-induced ROS release is considered a key pathogenic component for necrotizing small vessel vasculitis. However, our data underscore the need to study candidate mechanisms in complex in vivo conditions.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8][9][10] Numerous in vitro experiments suggest that phagocyte NADPH oxidase (Nox) and granule proteins, including neutrophil serine proteases (NSPs), participate in ANCA-mediated endothelial damage. 2,[11][12][13] We used a murine ANCA NCGN model and recently showed that IL-1b provides an important disease mediator and that proteolytically active NSPs are essential for processing pro-IL-1b to IL1b. 14 The in vivo role of phagocyte Nox (Phox) in NCGN is, however, not yet established.…”

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confidence: 99%

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Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

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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-1b 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-1b levels compared with mice transplanted with wild-type bone marrow. IL-1b receptor blockade abrogated aggravated NCGN in gp91 phox -deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1b generation in gp91 phox -deficient and p47 phox -deficient monocytes compared with wild-type monocytes. This enhanced IL-1b generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1b 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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

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“…A key role for neutrophil elastase has been postulated in models of lung injury due to its capacity to degrade extracellular matrix proteins and protease inhibitors [34]. A role for elastase in the pathogenesis of pulmonary injury in WG is well established: the protease has been found to be elevated in the BALF and in the circulation of patients with active disease [8,10], is liberated from neutrophils upon stimulation with anti-PR3 antibodies [15,17] and was recently found to mediate endothelial cell damage by ANCA-activated neutrophils in vitro [34], thus well in line with the present results.…”

Section: Cell and Animal Studies K Hattar Et Almentioning

confidence: 99%

c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis

Hattar¹,

Oppermann²,

Ankele³

et al. 2009

Eur Respir J

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Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI).In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3.Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCAinduced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury.In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase-and oxygen radicaldependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.

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“…In vitro, antineutrophil cytoplasmic antibodies (ANCAs) have been shown to activate neutrophils and monocytes, which can then cause endothelial cell damage (4,5). ANCA-primed leukocytes demonstrate augmented adherence to and transmigration across blood vessel walls (6).…”

mentioning

confidence: 99%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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Objective. T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO)antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness.Methods. MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed.Results. During disease remission, MPO-specific interferon-␥-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4؉CD25؉ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPOimmunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis.Conclusion. Our findings indicate that MPOspecific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.The antineutrophil cytoplasmic antibodyassociated vasculitides (AAV) are a group of relapsingremitting systemic diseases that result in considerable morbidity and mortality. Up to 25% of patients develop end-stage renal failure despite optimal immunosuppression. Understanding the immune mechanisms that regulate disease activity is critical for a more successful therapeutic approach to management of the disease. Recent work has highlighted the importance of both humoral and cellular effectors in disease pathogenesis. Pathogenic transplacental transfer of antimyeloperoxidase (anti-MPO) antibody to a neonate has been re-

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Mediation of endothelial cell damage by serine proteases, but not superoxide, released from antineutrophil cytoplasmic antibody–stimulated neutrophils

Cited by 46 publications

References 28 publications

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

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