Caspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis.
Immunity
; 52(6): 994-1006.e8, 2020 06 16.
Article
em En
| MEDLINE
| ID: mdl-32428502
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-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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Suscetibilidade a Doenças
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Caspase 8
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Proteína de Domínio de Morte Associada a Fas
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Necroptose
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Inflamação
Limite:
Animals
Idioma:
En
Revista:
Immunity
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos