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A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses.

Missense mutations of the gene encoding NLRP3 are associated with autoinflammatory disorders characterized with excessive production of interleukin-1beta (IL-1beta). Here we analyzed the immune responses of gene-targeted mice carrying a mutation in the Nlrp3 gene equivalent to the human mutation associated with Muckle-Wells Syndrome. We found that antigen-presenting cells (APCs) from such mice produced massive amounts of IL-1beta upon stimulation with microbial stimuli in the absence of ATP. This was likely due to a diminished inflammasome activation threshold that allowed a response to the small amount of agonist. Moreover, the Nlrp3 gene-targeted mice exhibited skin inflammation characterized by neutrophil infiltration and a Th17 cytokine-dominant response, which originated from hematopoietic cells. The inflammation of Nlrp3 gene-targeted mice resulted from excess IL-1beta production from APCs, which augmented Th17 cell differentiation. These results demonstrate that the NLRP3 mutation leads to inflammasome hyperactivation and consequently Th17 cell-dominant immunopathology in autoinflammation.

Pubmed ID: 19501001


  • Meng G
  • Zhang F
  • Fuss I
  • Kitani A
  • Strober W



Publication Data

June 19, 2009

Associated Grants

  • Agency: PHS HHS, Id: NIH0011985623

Mesh Terms

  • Adenosine Triphosphate
  • Animals
  • Antigen-Presenting Cells
  • CD4-Positive T-Lymphocytes
  • Carrier Proteins
  • Cell Differentiation
  • Cytokines
  • Inflammation
  • Interleukin-18
  • Interleukin-1beta
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Receptors, Antigen, T-Cell
  • Skin
  • T-Lymphocytes, Helper-Inducer