Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1β Activation and Severe Autoinflammation in Mice

摘要: Summary Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due loss an inhibitor inflammation or activity a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" harboring mutant human domains. Homozygous knockin, but not pyrin-deficient, exhibited spontaneous bone marrow-dependent similar more severe than FMF. Caspase-1 was constitutively activated knockin macrophages active IL-1β secreted when stimulated with lipopolysaccharide alone, which also observed patients. The inflammatory phenotype completely ablated by crossing IL-1 receptor-deficient adaptor molecule ASC-deficient mice, NLRP3-deficient mice. Thus, our data provide evidence for ASC-dependent NLRP3-independent inflammasome gain-of-function