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Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity.

NLRP3 nucleates the inflammasome, a protein complex responsible for cleavage of prointerleukin-1beta (IL-1beta) to its active form. Mutations in the NLRP3 gene cause the autoinflammatory disease spectrum cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1beta in CAPS is supported by the response to IL-1-targeted therapy. We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various gene mutant backgrounds showed that the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1beta, and was independent of T cells. These data suggest that CAPS are true inflammasome-mediated diseases and provide insight for more common inflammatory disorders.

Pubmed ID: 19501000

Authors

  • Brydges SD
  • Mueller JL
  • McGeough MD
  • Pena CA
  • Misaghi A
  • Gandhi C
  • Putnam CD
  • Boyle DL
  • Firestein GS
  • Horner AA
  • Soroosh P
  • Watford WT
  • O'Shea JJ
  • Kastner DL
  • Hoffman HM

Journal

Immunity

Publication Data

June 19, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI052430
  • Agency: NIAID NIH HHS, Id: R01 AI052430-06
  • Agency: NIAID NIH HHS, Id: R01 AI052430-07
  • Agency: NIAID NIH HHS, Id: R01 AI052430-08
  • Agency: NIAID NIH HHS, Id: R01-AI52430
  • Agency: NIAID NIH HHS, Id: R21 AI061108
  • Agency: NIAID NIH HHS, Id: R21 AI061108-01
  • Agency: NIAID NIH HHS, Id: R21 AI061108-02

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Carrier Proteins
  • Cytokines
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Immunity, Active
  • Immunity, Innate
  • Inflammation
  • Interleukin-18
  • Interleukin-1beta
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • T-Lymphocytes