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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Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
Virginie Pétrilli,Papin S,Catherine Dostert,Annick Mayor,Fabio Martinon,Fabio Martinon,J. Tschopp +6 more
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The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease
Yun-Hee Youm,Kim Y. Nguyen,Ryan W. Grant,Emily L. Goldberg,Monica Bodogai,Dongin Kim,Dominic P. D’Agostino,Noah J. Planavsky,Christopher R. Lupfer,Thirumala D. Kanneganti,Seokwon Kang,Tamas L. Horvath,Tarek M. Fahmy,Peter A. Crawford,Arya Biragyn,Emad S. Alnemri,Vishwa Deep Dixit +16 more
TL;DR: In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle–Wells syndrome, familial cold autoinflammatory syndrome and urate crystal–induced peritonitis and the findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of theNLRP3 inflammasome.
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