IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

Mutations in the gene encoding pyrin are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mutation (Mefv(V726A/V726A)) was generated to model human FMF. This mouse strain shows an autoinflammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC-mediated cell death leads to the release of IL-1 alpha and IL-1 beta, both of which signal through IL-1 receptor. Furthermore, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The specific IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion currently are unknown. In this study, we show that the autoinflammation observed in Maly(V726A/V726A) mice is mediated specifically by IL-1 beta and not IL-1 alpha. Furthermore, the disorder is dependent on the caspase-1 ASC axis, whereas caspase8 is dispensable. Concurrently, aberrant IL-1 beta release by Mefv(V726A/V726A) monocytes in response to stimulation with Lipopolysaccharide also is dependent on the caspase-1 ASC axis. In conclusion, our studies have uncovered a specific role for caspase-1-mediated IL-1 beta release in the manifestation of FMF.