Caspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis

• Published in: Immunity (Cambridge, Mass.) Mass.), 2020-06, Vol.52 (6), p.994-1006.e8
• Main Authors: Tummers, Bart, Mari, Luigi, Guy, Clifford S., Heckmann, Bradlee L., Rodriguez, Diego A., Rühl, Sebastian, Moretti, Julien, Crawford, Jeremy Chase, Fitzgerald, Patrick, Kanneganti, Thirumala-Devi, Janke, Laura J., Pelletier, Stephane, Blander, J. Magarian, Green, Douglas R.
• Format: Article
• Language: English
• Subjects: Ablation; Alleles; Animal pathology; Animals; Apoptosis; Apoptosis - genetics; autoimmune lymphoproliferative syndrome; Biomarkers; caspase; Caspase 8 - chemistry; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-1; Caspase-8; CD95 antigen; Cell death; Disease Models, Animal; Disease Progression; Disease Susceptibility; FADD; FADD protein; Fas-Associated Death Domain Protein - metabolism; FasL protein; Fluorescent Antibody Technique; Gene expression; Gene Expression Regulation; Inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - mortality; Inflammation - pathology; Lethality; Ligands; Lipopolysaccharides - adverse effects; Lipopolysaccharides - immunology; Lymphocytes; Mice; Mice, Knockout; Mortality; Mutation; Necroptosis; Necroptosis - genetics; Oligomerization; Phenotype; Protein Multimerization; Proteins; pyroptosis; Tumor necrosis factor-TNF
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.04.010

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-8F122GL123G/F122GL123G and non-cleavable Caspase-8D387A/D387A mutant mice with defective caspase-8-mediated apoptosis. Although neither mouse developed LPR disease, removal of the necroptosis effector Mlkl from Caspase-8D387A/D387A mice revealed an inflammatory role of caspase-8. Ablation of one allele of Fasl, Fadd, or Ripk1 prevented the pathology of Casp8D387A/D387AMlkl−/− 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. [Display omitted] •Non-cleavable caspase-8 (caspase-8 DA) causes inflammation, blocked by necroptosis•Inflammation in Casp8DA/DAMlkl−/− mice is prevented by ablation of one allele of Fadd•Full deletion of Fadd in Casp8DA/DAMlkl−/− mice causes Casp1-dependent lethality•Non-cleavable caspase-8 induces ASC oligomerization in absence of FADD Caspase-8 mediates apoptosis and blocks necroptosis. Additionally, Tummers et al. describe two ways in which caspase-8 triggers inflammatory signaling in vivo. Caspase-8 mediates CD95-induced inflammation in complex with its adaptor FADD. Furthermore, caspase-8 mediates inflammasome activation independently of FADD in epithelial cells. Both processes are blocked by auto-cleavage of the caspase.