Pathogen-Induced Interleukin-1β Processing and Secretion Is Regulated by a Biphasic Redox Response

Tassi, Sara; Carta, Sonia; Venè, Roberta; Delfino, Laura; Ciriolo, Maria Rosa; Rubartelli, Anna

doi:10.4049/jimmunol.0900578

Cited by 90 publications

(137 citation statements)

References 38 publications

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“…SOD-1-deficient mice produced less IL-1β in vivo and were less susceptible to LPS-induced shock (31). Another recent study demonstrated that silencing SOD-1 in human monocytes results in a reduction of IL-1β secretion on stimulation with zymosan (32). Taken together, these data are in agreement with our findings and strongly suggest that ROS inhibit inflammasome activation and, subsequently, IL-1β production.…”

Section: Discussionsupporting

confidence: 92%

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

Veerdonk

Smeekens

Joosten

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

224

162

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Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1β via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1β inflammasome in cells from CGD patients. In contrast to previous studies using the small molecule diphenylene iodonium (DPI) as a ROS inhibitor, we found no decrease in either caspase-1 activation or secretion of IL-1β and IL-18 in primary CGD monocytes. Moreover, activation of CGD monocytes by uric acid crystals induced a 4-fold higher level of IL-1β secretion compared with that seen in monocytes from unaffected subjects, and this increase was not due to increased synthesis of the IL-1β precursor. In addition, Western blot analysis of CGD cells revealed that caspase-1 activation was not decreased, but rather was increased compared with control cells. Examination of the effects exerted by the inhibition of ROS activity by DPI revealed that the decrease in IL-1β secretion by DPI was actually due to inhibition of IL-1β gene expression. Thus, inconsistent with the proinflammatory role of ROS, the present findings support the concept that ROS likely dampen inflammasome activation. The absence of ROS in CGD monocytes may explain the presence of an inflammatory phenotype characterized by granulomas and inflammatory bowel disease occurring in CGD patients.antioxidants | colitis | gout | inflammation | uric acid

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Section: Discussionsupporting

confidence: 92%

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

Veerdonk

Smeekens

Joosten

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

224

162

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“…These studies suggested that ROS generated upon TLR stimulation trigger an antioxidant response that is ultimately required for IL-1β secretion. The authors found that the inhibition of the antioxidant response did not induce intracellular accumulation of mature IL-1β in a cell where IL-1β processing is temporally coupled to secretion, suggesting that the antioxidant response is required for IL-1β processing [34]. We found notable differences in the regulation of IL-1β processing and secretion between neutrophils and those reported for monocytes.…”

Section: Discussioncontrasting

confidence: 48%

“…These contrasting findings might be due to differences in the mechanisms involved in the exportation of IL-1β out of the cell between mononuclear phagocytes and neutrophils, an issue that deserves further investigation. Previous work in monocytes showed that diphenyliodonium, a NADPH oxidase inhibitor, reduced IL-1β secretion [33,34]. These studies suggested that ROS generated upon TLR stimulation trigger an antioxidant response that is ultimately required for IL-1β secretion.…”

mentioning

confidence: 91%

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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“…6E). Because ROS production is generally counteracted by upregulation of antioxidant defenses to avoid oxidative stress [30], we analyzed the modulation of intracellular glutathione (GSH). GSH was absent after 30 min of stimulation and reached a maximum at 1 h (Fig.…”

Section: Inhibition Of Potassium Efflux Superoxide Production and Imentioning

confidence: 99%

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

et al. 2013

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In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL-1β and IL-18 production through inflammasome activation. This occurs via NLRP3 and caspase-1 activation, which cleaves pro-IL-1β into secreted bioactive IL-1β, a cytokine that was induced by Saps in monocytes, in monocyte-derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL-1β. Inflammasome activation required Sap internalization via a clathrin-dependent mechanism, intracellular induction of K + efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS-ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity.Keywords: Aspartic proteases r C. albicans r IL-1β r Inflammasome r Virulence factor IntroductionCandida albicans is a commensal fungus that colonizes human mucosal surfaces such as the vaginal and gastrointestinal tracts without causing harm. However, under conditions of primary or secondary immunodeficiency, this yeast can cause opportunistic infections such as mucosal inflammation and systemic sepsis [1]. The mortality rate associated with invasive candidiasis Correspondence: Dr. Anna Vecchiarelli e-mail: vecchiar@unipg.it has been reported to be as high as 40-50% [2]. Candida species are the fourth most common pathogens isolated from nosocomial bloodstream infections in the USA and Europe [3]. Although the immune status of the host plays a key role in the prevention or pathogenesis of C. albicans infections, a number of virulence attributes of C. albicans, such as factors that mediate adhesion, enzyme secretion, or hyphal formation, contribute to the disease process [4]. Particularly, the secretion of aspartic proteases (Saps), * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 680Donatella Pietrella et al. Eur. J. Immunol. 2013. 43: 679-692 which are encoded by a gene family with ten members, has long been recognized as a virulence-associated trait of this pathogenic yeast [5].We recently reported that various members of the Sap family, including Sap1, Sap2, Sap3, and Sap6, have different abilities to induce secretion of pro-inflammatory cytokines by human monocytes via Akt/NF-κB activation. Sap1, Sap2, and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Importantly, Sapinduced cytokine production was independent of the proteolytic activity and of the optimal pH for the individual Sap activities [6]. These data suggest ...

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Pathogen-Induced Interleukin-1β Processing and Secretion Is Regulated by a Biphasic Redox Response

Cited by 90 publications

References 38 publications

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

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

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

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

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