An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.

Journal Article (Journal Article)

The NLRP3 inflammasome plays a critical role in host defense by facilitating caspase I activation and maturation of IL-1β and IL-18, whereas dysregulation of inflammasome activity results in autoinflammatory disease. Factors regulating human NLRP3 activity that contribute to the phenotypic heterogeneity of NLRP3-related diseases have largely been inferred from the study of Nlrp3 mutant mice. By generating a mouse line in which the NLRP3 locus is humanized by syntenic replacement, we show the functioning of the human NLRP3 proteins in vivo, demonstrating the ability of the human inflammasome to orchestrate immune reactions in response to innate stimuli. Humanized mice expressing disease-associated mutations develop normally but display acute sensitivity to endotoxin and develop progressive and debilitating arthritis characterized by granulocytic infiltrates, elevated cytokines, erosion of bones, and osteoporosis. This NLRP3-dependent arthritis model provides a platform for testing therapeutic reagents targeting the human inflammasome.

Full Text

Duke Authors

Cited Authors

  • Snouwaert, JN; Nguyen, M; Repenning, PW; Dye, R; Livingston, EW; Kovarova, M; Moy, SS; Brigman, BE; Bateman, TA; Ting, JP-Y; Koller, BH

Published Date

  • December 13, 2016

Published In

Volume / Issue

  • 17 / 11

Start / End Page

  • 3077 - 3088

PubMed ID

  • 27974218

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2016.11.052


  • eng

Conference Location

  • United States