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

Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and “knockin” mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease. ► Pyrin mutant knockin (unlike deficient) mice exhibit marked neutrophilic inflammation ► There is constitutive inflammasome activation in knockin mice and FMF patients ► Autoinflammation in knockin mice is abrogated on the Il1r1 −/− background ► Deficiency in ASC, but not NLRP3 or RAG1, abrogates autoinflammation in knockin mice