NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy

Chengcheng Jin, Patrick Frayssinet, Richard Pelker, Diane Cwirka, Bo Hu, Agnès Vignery, Stephanie C. Eisenbarth, Richard A. Flavell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

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 airpouch 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.

Original languageEnglish (US)
Pages (from-to)14867-14872
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number36
DOIs
StatePublished - Sep 6 2011
Externally publishedYes

Keywords

  • ASC
  • Basic calcium phosphate crystals
  • Caspase-1

ASJC Scopus subject areas

  • General

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