Publication in detail

Immunity 2009 Jun 19;30(6):860-74. Epub 2009 Ju

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

Fuss, I; Kitani, A; Meng, G; Strober, W.; Zhang, F

Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract:
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.

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