| First Author | Tummers B | Year | 2020 |
| Journal | Immunity | Volume | 52 |
| Issue | 6 | Pages | 994-1006.e8 |
| PubMed ID | 32428502 | Mgi Jnum | J:296046 |
| Mgi Id | MGI:6466756 | Doi | 10.1016/j.immuni.2020.04.010 |
| Citation | Tummers B, et al. (2020) Caspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis. Immunity 52(6):994-1006.e8 |
| abstractText | Cell death pathways regulate various homeostatic processes. Autoimmune lymphoproliferative syndrome (ALPS) in humans and lymphoproliferative (LPR) disease in mice result from abrogated CD95-induced apoptosis. Because caspase-8 mediates CD95 signaling, we applied genetic approaches to dissect the roles of caspase-8 in cell death and inflammation. Here, we describe oligomerization-deficient Caspase-8(F122GL123G/F122GL123G) and non-cleavable Caspase-8(D387A/D387A) mutant mice with defective caspase-8-mediated apoptosis. Although neither mouse developed LPR disease, removal of the necroptosis effector Mlkl from Caspase-8(D387A/D387A) mice revealed an inflammatory role of caspase-8. Ablation of one allele of Fasl, Fadd, or Ripk1 prevented the pathology of Casp8(D387A/D387A)Mlkl(-/-) animals. Removing both Fadd alleles from these mice resulted in early lethality prior to post-natal day 15 (P15), which was prevented by co-ablation of either Ripk1 or Caspase-1. Our results suggest an in vivo role of the inflammatory RIPK1-caspase-8-FADD (FADDosome) complex and reveal a FADD-independent inflammatory role of caspase-8 that involves activation of an inflammasome. |
