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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    • "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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    • "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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