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An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.

Publication ,  Journal Article
Snouwaert, JN; Nguyen, M; Repenning, PW; Dye, R; Livingston, EW; Kovarova, M; Moy, SS; Brigman, BE; Bateman, TA; Ting, JP-Y; Koller, BH
Published in: Cell Rep
December 13, 2016

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.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

December 13, 2016

Volume

17

Issue

11

Start / End Page

3077 / 3088

Location

United States

Related Subject Headings

  • Osteoporosis
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mutation
  • Mice
  • Joint Diseases
  • Inflammasomes
  • Humans
  • Disease Models, Animal
  • Animals
  • 31 Biological sciences
 

Citation

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Snouwaert, J. N., Nguyen, M., Repenning, P. W., Dye, R., Livingston, E. W., Kovarova, M., … Koller, B. H. (2016). An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. Cell Rep, 17(11), 3077–3088. https://doi.org/10.1016/j.celrep.2016.11.052
Snouwaert, John N., MyTrang Nguyen, Peter W. Repenning, Rebecca Dye, Eric W. Livingston, Martina Kovarova, Sheryl S. Moy, et al. “An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.Cell Rep 17, no. 11 (December 13, 2016): 3077–88. https://doi.org/10.1016/j.celrep.2016.11.052.
Snouwaert JN, Nguyen M, Repenning PW, Dye R, Livingston EW, Kovarova M, et al. An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. Cell Rep. 2016 Dec 13;17(11):3077–88.
Snouwaert, John N., et al. “An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.Cell Rep, vol. 17, no. 11, Dec. 2016, pp. 3077–88. Pubmed, doi:10.1016/j.celrep.2016.11.052.
Snouwaert JN, Nguyen M, Repenning PW, Dye R, Livingston EW, Kovarova M, Moy SS, Brigman BE, Bateman TA, Ting JP-Y, Koller BH. An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. Cell Rep. 2016 Dec 13;17(11):3077–3088.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

December 13, 2016

Volume

17

Issue

11

Start / End Page

3077 / 3088

Location

United States

Related Subject Headings

  • Osteoporosis
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mutation
  • Mice
  • Joint Diseases
  • Inflammasomes
  • Humans
  • Disease Models, Animal
  • Animals
  • 31 Biological sciences