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

Immunity | Jun 19, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19501001

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 RIS Download

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

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Associated grants

  • Agency: PHS HHS, Id: NIH0011985623

Mouse Genome Informatics (Data, Gene Annotation)

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