Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp JGout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237-241

Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Nature (Impact Factor: 41.46). 04/2006; 440(7081):237-41. DOI: 10.1038/nature04516
Source: PubMed


Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

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    • "Macrophages signaled through TLR2 and TLR4 showed significantly decreased expression of proinflammatory cytokines including IL-1í µí»½ and TNF-í µí»¼ [22]. Intracellular engagement of TLR-mediated MSU crystals induces the release of pro-IL-í µí»½ via NF-í µí¼…B activation and promotes the NALP3 inflammasome to drive caspase-1 activation, leading to secretion of active IL-1í µí»½ [23] [24]. A recombinant IL-1 receptor antagonist (anakinra) and IL-1 TRAP were shown to be effective in patients with acute and chronic gouty inflammation [25] [26]. "
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    ABSTRACT: The aim of this study was to clarify the role of monosodium urate (MSU) crystals in receptor activator of nuclear factor kB ligand- (RANKL-) RANK-induced osteoclast formation. RAW 264.7 murine macrophage cells were incubated with MSU crystals or RANKL and differentiated into osteoclast-like cells as confirmed by staining for tartrate-resistant acid phosphatase (TRAP) and actin ring, pit formation assay, and TRAP activity assay. MSU crystals in the presence of RANKL augmented osteoclast differentiation, with enhanced mRNA expression of NFATc1, cathepsin K, carbonic anhydrase II, and matrix metalloproteinase-9 (MMP-9), in comparison to RAW 264.7 macrophages incubated in the presence of RANKL alone. Treatment with both MSU crystals and RANKL induced osteoclast differentiation by activating downstream molecules in the RANKL-RANK pathway including tumor necrosis factor receptor-associated factor 6 (TRAF-6), JNK, c-Jun, and NFATc1. IL-1b produced in response to treatment with both MSU and RANKL is involved in osteoclast differentiation in part through the induction of TRAF-6 downstream of the IL-1b pathway. This study revealed that MSU crystals contribute to enhanced osteoclast formation through activation of RANKL-mediated pathways and recruitment of IL-1b. These findings suggest that MSU crystals might be a pathologic causative agent of bone destruction in gout.
    Full-text · Article · Sep 2015 · Mediators of Inflammation
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    • "It represents a multimeric protein complex containing a NLR molecule, the adaptor molecule apoptosisassociated speck-like protein (ASC) containing a caspase activating and recruitment domain (CARD) and pro-caspase-1. The NLRP3 inflammasome is activated in response to numerous PAMPs and DAMPs, including bacterial RNA and toxins (Kanneganti et al., 2006a,2006b), K 1 efflux, extracellular ATP (Mariathasan et al., 2006), uric acid (Martinon et al., 2006), amyloid-b (Halle, 2008), and mitochondrial reactive oxygen species (mROS) (Martinon, 2010). NLRP3 is essential for the production of interleukin (IL) IL1b and IL18, and is considered as an effective target for modulating the initiation and progression of neuroinflammation. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motoneurons in the cerebral cortex, brainstem and spinal cord. Neuroinflammation plays an important role in the pathogenesis of ALS and involves the activation of microglia and astrocytes. Intracellular inflammasome complexes are part of the innate immunity as they sense and execute host inflammatory responses. The best characterized component is the NLRP3 inflammasome comprised of the NLR protein NLRP3, the adaptor ASC and pro-caspase 1. The NLRP3 inflammasome is critical for the activation of caspase 1 and the processing and release of IL1β and IL18. In this study, we investigated the expression, activation and co-localization of the NLRP3 inflammasome in the spinal cord of male SOD1(G93A) mice carrying a mutant human superoxide dismutase 1 (SOD1) variant and regarded as an animal model for ALS as well as in post-mortem tissue of ALS patients. NLRP3 and its molecular components as well as IL1β were already detectable in SOD1 mice at a pre-symptomatic stage after 9 weeks and further increased in 14 week old animals. Spinal cord astrocytes were identified as the major cell type expressing NLRP3 components. In human ALS tissue, we also found increased NLRP3, ASC, IL18 and active caspase 1 levels compared to control patients. Our findings suggest that astroglial NLRP3 inflammasome complexes are critically involved in neuroinflammation in ALS. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · Glia
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    • "Inhibition of NALP3 inflammasome and innate immune responses MSU and calcium pyrophosphate dihydrate crystals (CPPD) were shown to specifically activate the NALP3 inflammasome, also known as the cryopyrin inflammasome. At high concentrations (5 μM), colchicine suppresses MSU-induced NALP3 inflammasomes , responsible for caspase-1 activation and subsequent IL1β and IL18 processing and release [20]. The mechanism by which colchicine inhibits this NALP3 inflammasome activation is still unknown. "
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    ABSTRACT: To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. Copyright © 2015 Elsevier Inc. All rights reserved.
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