Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Nature Immunology (Impact Factor: 24.97). 12/2009; 11(2):136-40. DOI: 10.1038/ni.1831
Source: PubMed

ABSTRACT The NLRP3 inflammasome has a major role in regulating innate immunity. Deregulated inflammasome activity is associated with several inflammatory diseases, yet little is known about the signaling pathways that lead to its activation. Here we show that NLRP3 interacted with thioredoxin (TRX)-interacting protein (TXNIP), a protein linked to insulin resistance. Inflammasome activators such as uric acid crystals induced the dissociation of TXNIP from thioredoxin in a reactive oxygen species (ROS)-sensitive manner and allowed it to bind NLRP3. TXNIP deficiency impaired activation of the NLRP3 inflammasome and subsequent secretion of interleukin 1beta (IL-1beta). Akin to Txnip(-/-) mice, Nlrp3(-/-) mice showed improved glucose tolerance and insulin sensitivity. The participation of TXNIP in the NLRP3 inflammasome activation may provide a mechanistic link to the observed involvement of IL-1beta in the pathogenesis of type 2 diabetes.

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    • "Inflammasome can be activated in the liver in both liver-resident cells (Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells), and immune cells (monocytes, macrophages , dendritic cells, natural killer cells) contributing to the apoptotic or necrotic demise of hepatocytes (Brenner et al., 2013). Several inflammasome complexes exist and among them, the NALP-3 inflammasome has been shown recently to be directly activated by the presence of sustained amounts of ROS (Zhou et al., 2010). Furthermore , the oxidative damage produced by free radicals also promotes the activation of NALP-3 inflammasome (Martinon, 2010). "
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    ABSTRACT: Inflammation is a hallmark of aging. Caloric restriction and resveratrol (RSV) have shown important effects on prevention of oxidative stress and inflammation. Here, we investigate the progression of proinflammatory markers in liver during aging and the effect of RSV on inflammation markers in liver of old male C57BL/6J mice. Young (2 months), mature (12 months) and old (18 months) mice were fed during 6 months with RSV. Levels of IL-1β, IL-6, IL-10, IL-17 and TNF-α were evaluated by ELISA in mice liver. Levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17 and TNF-α and also their respective mRNA increased in liver from old mice. However, RSV decreased these levels in the case of IL-1β and TNF-α but only in old mice showing no effect on young and mature animals. This reduction was also found at the mRNA level. Levels of mRNA of the components of NALP-3 inflammasome, ASC, CASP-1, NALP-1 and NALP-3, also showed an age-dependent increase that was reversed by RSV. Furthermore, cyclooxygenase 2 levels, a marker of proinflammatory innate immune activity, were also upregulated in aged liver and reversed again by RSV. In conclusion, our study confirms that aging is accompanied by an increase in the proinflammatory pattern in liver and that RSV reduces this pattern in old mice liver. Copyright © 2015 Elsevier B.V. All rights reserved.
    Experimental Gerontology 02/2015; 64. DOI:10.1016/j.exger.2015.02.004 · 3.53 Impact Factor
    • "Endogenous danger signals (DAMPs) Extracellular ATP ROS and channel formation Cruz et al. (2007) Hyluronan Not yet determined Glucose ROS Zhou et al. (2010) MSU ROS Pétrilli et al. (2007) CPPD Not yet determined A␤ ROS and lysosome rupture Parajuli et al. (2013), Halle et al. (2008) Environmental irritants Skin irritants and UV ROS Bossi et al. (2008) Silica ROS and lysosome rupture Dostert et al. (2008), Hornung et al. (2008) Asbestos ROS Dostert et al. (2008) Alum ROS and lysosome rupture Hornung et al. (2008) Endogenous Microbial Signals (MAMPs) "
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    ABSTRACT: Accumulating evidence indicates that aging is associated with a chronic low-level inflammation, termed sterile-inflammation. Sterile-inflammation is a form of pathogen-free inflammation caused by mechanical trauma, ischemia, stress or environmental conditions such as ultra-violet radiation. These damage-related stimuli induce the secretion of molecular agents collectively termed danger-associated molecular patterns (DAMPs). DAMPs are recognized by virtue of specialized innate immune receptors, such as toll-like receptors (TLRs) and NOD-like receptor family, pyrin domain containing 3 (NLRP3). These receptors initiate signal transduction pathways, which typically drive inflammation in response to microbe-associated molecular patterns (MAMPs) and/or DAMPs. This review summarizes the current knowledge on DAMPs-mediated sterile-inflammation, its associated downstream signaling, and discusses the possibility that DAMPs activating TLRs or NLRP3 complex mediate sterile inflammation during aging and in aging-related pathologies. Copyright © 2015. Published by Elsevier B.V.
    Ageing Research Reviews 01/2015; DOI:10.1016/j.arr.2015.01.003 · 7.63 Impact Factor
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    • "Where tested, the effects of NLRP3 deficiency on diabetes in mice are partially phenocopied by IL-1R deficiency (Masters et al. 2010). Furthermore , inhibition of NLRP3 inflammasome activation ameliorated metabolic changes associated with HFD (Stienstra et al. 2010; Zhou et al. 2010). In humans, proof-of-concept studies have suggested that IL-1 blockade may significantly ameliorate T2D (Larsen et al. 2007), and larger-scale clinical trials are underway to definitively determine the potential of this treatment strategy (Boni-Schnetzler and Donath 2013). "
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    ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
    Cold Spring Harbor perspectives in biology 10/2014; 6(12). DOI:10.1101/cshperspect.a016287 · 8.23 Impact Factor
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