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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Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.
Fátima Martín-Sánchez,Catherine Emma Diamond,Catherine Emma Diamond,Marcel Zeitler,Ana I. Gomez,Alberto Baroja-Mazo,James Bagnall,David G. Spiller,Michael R. H. White,Michael J.D. Daniels,Alessandra Mortellaro,M Peñalver,Pawel Paszek,Julia P. Steringer,Walter Nickel,David Brough,Pablo Pelegrín +16 more
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Basic Calcium Phosphate Crystals Induce Monocyte/Macrophage IL-1β Secretion through the NLRP3 Inflammasome In Vitro
Borbála Pazár,Hang-Korng Ea,Hang-Korng Ea,Sharmal Narayan,Laeticia Kolly,Nathalie Bagnoud,Véronique Chobaz,Thierry Roger,Frédéric Lioté,Frédéric Lioté,Alexander So,Nathalie Busso +11 more
TL;DR: Results demonstrate that BCP crystals induce IL-1β secretion through activating the NLRP3 inflammasome and speculate that IL- 1 blockade could be a novel strategy to inhibit BCP-induced inflammation in human disease.
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