Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease

Veerdonk, Frank L. van de; Smeekens, Sanne P.; Joosten, Leo A. B.; Kullberg, Bart Jan; Dinarello, Charles A.; Meer, J.W.M. van der; Netea, Mihai G.

doi:10.1073/pnas.0914795107

Cited by 228 publications

(186 citation statements)

References 35 publications

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“…31 More recently, it was shown in patients that Phox deficiency caused increased caspase-1 activity and IL-1b generation. 32,33 However, this issue remains a matter of debate, because several groups showed that ROS had either no effect or an accelerating effect on inflammasome-mediated IL-1b. [34][35][36] Furthermore, the ROS source and the specific ROS molecule that controls inflammasome activity are not yet characterized.…”

Section: Discussionmentioning

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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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%

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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“…Previous studies in monocytes and macrophages established that caspase-1 activity is negatively regulated by cysteine oxidation [12,28]. As pro-IL-1β processing takes place before mature IL-1β is released from cells by the ROS-dependent mechanism described above, we reasoned that if neutrophil caspase-1 is also regulated by oxidation, the addition of superoxide before neutrophil stimulation should inhibit pro-IL-1β processing and consequently IL-1β secretion.…”

Section: Ros Also Negatively Regulate Neutrophil Pro-il-1β Processingmentioning

confidence: 99%

NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL‐1β secretion but not in inflammasome activation

et al. 2013

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Neutrophils are essential players in acute inflammatory responses. Upon stimulation, neutrophils activate NADPH oxidase, generating an array of reactive oxygen species (ROS).Interleukin-1 beta (IL-1β) is a major proinflammatory cytokine synthesized as a precursor that has to be proteolytically processed to become biologically active. The role of ROS in IL-1β processing is still controversial and has not been previously studied in neutrophils. We report here that IL-1β processing in human neutrophils is dependent on caspase-1 and on the serine proteases elastase and/or proteinase 3. NADPH oxidase deficient neutrophils activated caspase-1 and did not exhibit differences in NALP3 expression, indicating that ROS are neither required for inflammasome activation nor for its priming, as has been reported for macrophages. Strikingly, ROS exerted opposite effects on the processing and secretion of IL-1β; whereas ROS negatively controlled caspase-1 activity, as reported in mononuclear phagocytes, ROS were found to be necessary for the exportation of mature IL-1β out of the cell, a role never previously described. The complex ROS-mediated regulation of neutrophil IL-1β secretion might constitute a physiological mechanism to control IL-1β-dependent inflammatory processes where neutrophils play a crucial role.Keywords: Caspase-1 r IL-1β r NADPH-oxidase r Neutrophil r Reactive oxygen species Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNeutrophils represent the first line of defense against bacterial and fungal infections. Their pivotal role is highlighted by recurCorrespondence: Dr. Analía S. Trevani e-mail: analiatrevani@yahoo.com.ar rent infections in individuals suffering from neutrophil functional disorders or neutropenia [1]. Neutrophils kill microbes by the release of destructive molecules such as proteases and highly reactive oxygen species (ROS), and can also produce a variety of proteins, including cytokines, chemotactic molecules, and other mediators that are involved in their effector functions [2]. However, the microbicidal effectiveness of neutrophils is sometimes obscured by the damage suffered by adjacent healthy tissues; this is a price that has to be paid to contain potentially C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3324-3335 Innate Immunity 3325 life-threatening situations [3]. Although infections are the major triggers of neutrophil recruitment, many different sterile stimuli, including mechanical trauma, ischemia, toxins, minerals, crystals, and chemicals also lead to neutrophil accumulation in the tissues. In these situations, neutrophils may contribute to inflict collateral damage on otherwise healthy cells [3]. Interleukin-1 beta (IL-1β) is a key cytokine involved in the development of neutrophilic inflammation induced either by microbial or sterile inflammatory stimuli. It is a potent multifunctional proinflammatory cytokine, whose activity is controlled at the le...

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“…*P , .05, **P , .01, ****P , .0001. IL-1b when stimulated in vitro with particulate and soluble activators of caspase-1 and NLRP3 inflammasome, 44,47,48 and 1 study reported increased IL-1a release by LPS-stimulated human CGD monocytes. 47 Here, we showed that NADPH oxidase deficiency augmented IL-1a and IL-1b release from murine resident macrophages, BMDMs, and BMDCs challenged with classic DAMPs that activate the NLRP3 inflammasome.…”

Section: Org Frommentioning

confidence: 99%