title: IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever.
abstract: 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 (MefvV726A/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-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 MefvV726A/V726Amice 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 MefvV726A/V726Amonocytes 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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Bhesh Raj
authors.initials: BR
authors.lastname: Sharma
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address: thirumala-devi.kanneganti@stjude.org.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D010505:Familial Mediterranean Fever / Q000276:immunology*; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D053583:Interleukin-1beta / Q000276:immunology*; D051379:Mice
chemical_list: D053583:Interleukin-1beta; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020170:Caspase 1