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 in kidney disease and autoimmunity
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Update on colchicine, 2017.
Anastasia Slobodnick,Anastasia Slobodnick,Binita Shah,Binita Shah,Svetlana Krasnokutsky,Svetlana Krasnokutsky,Michael H. Pillinger,Michael H. Pillinger +7 more
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Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study
Nicola Dalbeth,Meaghan E House,Opetaia Aati,Paul Tan,Christopher S. Franklin,Anne Horne,Gregory D. Gamble,Lisa K. Stamp,Anthony Doyle,Fiona M McQueen +9 more
TL;DR: The data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs in people with asymptomatic hyperuricaemia and symptomatic gout.
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Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2
Noemí Marina-García,Luigi Franchi,Yun Gi Kim,Douglas Miller,Christine McDonald,Geert-Jan Boons,Gabriel Núñez +6 more
TL;DR: It is shown that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments and a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation is demonstrated.
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