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

被引：106

作者：

Tummers, Bart ^{[1
]}

Mari, Luigi ^{[1
]}

Guy, Clifford S. ^{[1
]}

Heckmann, Bradlee L. ^{[1
]}

Rodriguez, Diego A. ^{[1
]}

Ruhl, Sebastian ^{[1
]}

Moretti, Julien ^{[3
]}

Crawford, Jeremy Chase ^{[1
]}

Fitzgerald, Patrick ^{[1
]}

Kanneganti, Thirumala-Devi ^{[1
]}

Janke, Laura J. ^{[2
]}

Pelletier, Stephane ^{[1
]}

Blander, J. Magarian ^{[3
,4
,5
,6
]}

Green, Douglas R. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Immunol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Pathol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[3] Cornell Univ, Jill Roberts Inst Res Inflammatory Bowel Dis, Weill Cornell Med, New York, NY 10021 USA

[4] Cornell Univ, Joan & Sanford I Weill Dept Med, Gastroenterol & Hepatol Div, Weill Cornell Med, New York, NY 10021 USA

[5] Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10021 USA

[6] Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY 10021 USA

来源：

IMMUNITY | 2020年 / 52卷 / 06期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; NLRP3; INFLAMMASOME; PSEUDOKINASE MLKL; MOLECULAR SWITCH; CASPASE-8; IL-1-BETA; APOPTOSIS; ACTIVATION; MATURATION; ROLES;

D O I：

10.1016/j.immuni.2020.04.010

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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)(/D3)(87A) mutant mice with defective caspase-8-mediated apoptosis. Although neither mouse developed LPR disease, removal of the necroptosis effector MIkl 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.

引用

页码：994 / +

页数：21

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