Gout-associated uric acid crystals activate the NALP3 inflammasome
TLDR
It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.Abstract:
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.read more
Citations
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The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia.
Martin Witzenrath,Florence Pache,Daniel Lorenz,Uwe Koppe,Birgitt Gutbier,Christoph Tabeling,Katrin Reppe,Karolin Meixenberger,Anca Dorhoi,Jiangtao Ma,Ashleigh Holmes,George Trendelenburg,Markus M. Heimesaat,Stefan Bereswill,Mark van der Linden,Jürg Tschopp,Timothy J. Mitchell,Norbert Suttorp,Bastian Opitz +18 more
TL;DR: The inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease, and indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.
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MCC950 closes the active conformation of NLRP3 to an inactive state.
Ana Tapia-Abellán,Diego Angosto-Bazarra,Helios Martínez-Banaclocha,Carlos de Torre-Minguela,José P. Cerón-Carrasco,Horacio Pérez-Sánchez,Juan I. Aróstegui,Pablo Pelegrín +7 more
TL;DR: MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, inactivatesNLRP3, including hyperactive disease-linked mutations, by closing the ‘open’ conformation, thereby preventing conformational changes required for NLRP2 activation.
Journal ArticleDOI
Molecular mechanisms of inflammasome activation during microbial infections.
Petr Broz,Denise M. Monack +1 more
TL;DR: The inflammasome serves as an activation platform for the mammalian cysteine protease caspase-1, which is a central mediator of innate immunity.
Journal ArticleDOI
β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares
Emily L. Goldberg,Jennifer L. Asher,Ryan D. Molony,Albert C. Shaw,Caroline J. Zeiss,Chao Wang,Ludmilla A. Morozova-Roche,Raimund I. Herzog,Akiko Iwasaki,Vishwa Deep Dixit +9 more
TL;DR: KD increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection and studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
Journal ArticleDOI
Soluble Uric Acid Activates the NLRP3 Inflammasome
Tarcio Teodoro Braga,Maria Fernanda Forni,Matheus Correa-Costa,Rodrigo Nalio Ramos,José Alexandre Marzagão Barbuto,Paola Cristina Branco,Angela Castoldi,Meire Ioshie Hiyane,Mariana Rodrigues Davanso,Eicke Latz,Bernardo S. Franklin,Alicia J. Kowaltowski,Niels Olsen Saraiva Camara,Niels Olsen Saraiva Camara +13 more
TL;DR: Findings suggest sUA activates the NLRP3 inflammasome and it is proposed that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.
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