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