Gout-associated uric acid crystals activate the NALP3 inflammasome.
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.
Martinon
Fabio
F
Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Pétrilli
Virginie
V
Mayor
Annick
A
Tardivel
Aubry
A
Tschopp
Jürg
J
D000818:Animals; D002131:Calcium Pyrophosphate / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003078:Colchicine / Q000494:pharmacology; D004195:Disease Models, Animal; D006073:Gout / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; D014527:Uric Acid; D020170:Caspase 1; D003078:Colchicine; D002131:Calcium Pyrophosphate