title: NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy.
abstract: The proinflammatory and catabolic cytokine IL-1β has been implicated in the pathogenesis of osteoarthritis (OA) by mediating synovial inflammation and cartilage degeneration. Although synovial macrophages are suggested to be the source of IL-1β, the mechanism remains unclear. Ectopic deposition of hydroxyapatite (HA) crystals in joints is closely associated with OA and other arthropathies, but the precise role of HA in arthritis pathogenesis has not been clearly demonstrated. Here we show that HA crystals of a particular size and shape can stimulate robust secretion of proinflammatory cytokines IL-1β and IL-18 from murine macrophages in a NLRP3 inflammasome-dependent manner. HA-induced inflammasome activation is dependent on potassium efflux, generation of reactive oxygen species (ROS), and lysosomal damage, but independent of cell death. Mice lacking the inflammasome components are protected against HA-induced neutrophilic inflammation in the air-pouch model of synovitis, and they show decreased joint pathology accompanying spontaneous HA deposition in the ank-deficient mouse model of arthritis. Moreover, calcium crystal positive synovial fluids from some OA patients exhibited inflammasome-stimulatory activity in vitro. These results demonstrate that the NLRP3 inflammasome mediates the pathological effect of HA crystals in vitro and in vivo and suggest a critical role for the inflammasome in the pathogenesis of OA.
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Jin
authors.forename: Patrick
authors.initials: P
authors.lastname: Frayssinet
authors.forename: Richard
authors.initials: R
authors.lastname: Pelker
authors.forename: Diane
authors.initials: D
authors.lastname: Cwirka
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Agnès
authors.initials: A
authors.lastname: Vignery
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D017886:Durapatite / Q000009:adverse effects* / Q000494:pharmacology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics; D010003:Osteoarthritis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028061:Phosphate Transport Proteins / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D001672:Biocompatible Materials; D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D028061:Phosphate Transport Proteins; D017382:Reactive Oxygen Species; C410982:ank protein, mouse; D017886:Durapatite; D011188:Potassium