| First Author | Sharma D | Year | 2017 |
| Journal | Am J Pathol | Volume | 187 |
| Issue | 2 | Pages | 236-244 |
| PubMed ID | 27998728 | Mgi Jnum | J:240185 |
| Mgi Id | MGI:5882631 | Doi | 10.1016/j.ajpath.2016.10.015 |
| Citation | Sharma D, et al. (2017) IL-1beta and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1alpha or Caspase-8 in a Mouse Model of Familial Mediterranean Fever. Am J Pathol 187(2):236-244 |
| abstractText | 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-1alpha and IL-1beta, 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/V726A mice is mediated specifically by IL-1beta and not IL-1alpha. Furthermore, the disorder is dependent on the caspase-1-ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1beta release by MefvV726A/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-1beta release in the manifestation of FMF. |
