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

TitleCaspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis.
Publication TypeJournal Article
Year of Publication2020
AuthorsTummers, B, Mari, L, Guy, CS, Heckmann, BL, Rodriguez, DA, Rühl, S, Moretti, J, Crawford, JChase, Fitzgerald, P, Kanneganti, T-D, Janke, LJ, Pelletier, S, J Blander, M, Green, DR
JournalImmunity
Volume52
Issue6
Pagination994-1006.e8
Date Published2020 Jun 16
ISSN1097-4180
Abstract

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 and non-cleavable Caspase-8 mutant mice with defective caspase-8-mediated apoptosis. Although neither mouse developed LPR disease, removal of the necroptosis effector Mlkl from Caspase-8 mice revealed an inflammatory role of caspase-8. Ablation of one allele of Fasl, Fadd, or Ripk1 prevented the pathology of Casp8Mlkl 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.

DOI10.1016/j.immuni.2020.04.010
Alternate JournalImmunity
PubMed ID32428502
PubMed Central IDPMC7306001
Grant ListR01 AI044828 / AI / NIAID NIH HHS / United States
R01 AI127658 / AI / NIAID NIH HHS / United States
R35 CA231620 / CA / NCI NIH HHS / United States
R37 AI044828 / AI / NIAID NIH HHS / United States