Cutting Edge: Reactive Oxygen Species Inhibitors Block Priming, but Not Activation, of the NLRP3 Inflammasome

Bauernfeind, Franz; Bartok, Eva; Rieger, Anna; Franchi, Luigi; Núñez, Gabriel; Hornung, Veit

doi:10.4049/jimmunol.1100613

Cited by 525 publications

(491 citation statements)

References 24 publications

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“…It was found that DPI inhibited IL-1β production in a dose-dependent manner ( Figure 1P). Of note was that DPI treatment affected the production of IL-8 similarly, which was in line with a recent study showing that ROS inhibitors, including DPI, interfere with NF-κB signaling (Supplementary information, Figure S4A) [12]. Moreover, as Cathepsin B activity was also involved in the response of various stimulus-induced inflammasome activation [13], we tested the possibility that it might be also required for C. neoformans biofilm-induced NLRP3 inflammasome activation.…”

supporting

confidence: 55%

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

Lei

Chen

et al. 2013

Cell Res

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supporting

confidence: 55%

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

Lei

Chen

et al. 2013

Cell Res

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“…Bauernfeind et al [30] in macrophages showed that once NLRP3 was expressed, ROS inhibition had no impact on IL-1β release. By contrast, in PLB cells, we observed that ROS deficiency affected neither NLRP3 expression nor inflammasome activation upon stimulation, but did cause a reduction in the ability of PLB-KO cells to secrete IL-1β, evidencing a never before described role of ROS on the release of mature IL-1β.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies by Bauernfeind et al [30] in mouse macrophages showed that ROS produced by LPS priming are required to induce NALP3 expression and consequently for caspase-1 activation. By contrast, results of our study showed that human neutrophils express NALP3 and this expression is not markedly increased by LPS treatment.…”

Section: Discussionmentioning

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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“…S100A8/S100A9 heterodimers activate both NF-kB and NLRP3 inflammasome assembly via a NOX/ROS-dependent mechanism. 23,[44][45][46] Intracellularly, S100A8/9 heterodimers serve as a scaffold for the membrane assembly and activation of the NOX complex, 47,48 which generates ROS via transfer of electrons across membranes to generate superoxide. 49 As also shown here, NOX regulates both priming and activation of NLRP3 inflammasomes, including the activation of caspase-1 and IL-1b secretion.…”

Section: Discussionmentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

284

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Cutting Edge: Reactive Oxygen Species Inhibitors Block Priming, but Not Activation, of the NLRP3 Inflammasome

Cited by 525 publications

References 24 publications

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

Biofilm from a clinical strain of Cryptococcus neoformans activates the NLRP3 inflammasome

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

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

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