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) 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-1α and IL-1β, 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 Mefv mice is mediated specifically by IL-1β and not IL-1α. Furthermore, the disorder is dependent on the caspase-1-ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1β release by Mefv 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-1β release in the manifestation of FMF.