美国圣裘德儿童研究医院Douglas R. Green研究组在研究中取得进展。他们表明Caspase-8依赖性炎症反应受其受体、FADD和细胞坏死的控制。这一研究成果发表在2020年5月18日的《免疫学》上。

他们描述了寡聚缺陷Caspase-8F122GL123G / F122GL123G和不可切割的Caspase-8D387A / D387A突变小鼠，它们具有缺陷的caspase-8介导的细胞凋亡活性。尽管这两只小鼠均未患有LPR疾病，但从Caspase-8D387A / D387A小鼠中去除细胞坏死效应因子Mlk1却显示出caspase-8的炎症作用。Fasl，Fadd或Ripk1中，任一等位基因的缺失阻止了Casp8D387A / D387AMlk1-/-动物的病理。从这些小鼠中去除两个Fadd等位基因均导致出生后第15天（P15）之前的早期死亡，这可以通过共同敲除Ripk1或Caspase-1来阻止。

他们的结果表明炎症性RIPK1-caspase-8-FADD（FADDosome）复合物的体内作用，并揭示了caspase-8的FADD非依赖性炎症作用，这涉及炎症小体的激活。

据悉，细胞死亡途径调节各种稳态过程。人类自身免疫性淋巴组织增生综合征（ALPS）和小鼠淋巴组织增生性（LPR）疾病是由CD95诱导的细胞凋亡消除导致的。因为caspase-8介导CD95信号传导，所以他们应用遗传方法剖析了caspase-8在细胞死亡和炎症中的作用。

附：英文原文

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

Author: Bart Tummers, Luigi Mari, Clifford S. Guy, Bradlee L. Heckmann, Diego A. Rodriguez, Sebastian Rühl, Julien Moretti, Jeremy Chase Crawford, Patrick Fitzgerald, Thirumala-Devi Kanneganti, Laura J. Janke, Stephane Pelletier, J. Magarian Blander, Douglas R. Green

Issue&Volume: 2020-05-18

Abstract: Cell death pathways regulate various homeostatic processes. Autoimmune lymphoproliferativesyndrome (ALPS) in humans and lymphoproliferative (LPR) disease in mice result fromabrogated CD95-induced apoptosis. Because caspase-8 mediates CD95 signaling, we appliedgenetic 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 developedLPR 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-independentinflammatory role of caspase-8 that involves activation of an inflammasome.

DOI: 10.1016/j.immuni.2020.04.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30168-0