The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis

被引：196
作者：
Alvarez-Diaz, Silvia [1 ,2 ]
Dillon, Christopher P. [3 ]
Lalaoui, Najoua [1 ,2 ]
Tanzer, Maria C. [1 ,2 ]
Rodriguez, Diego A. [3 ]
Lin, Ann [1 ]
Lebois, Marion [1 ]
Hakem, Razq [4 ,5 ]
Josefsson, Emma C. [1 ,2 ]
O'Reilly, Lorraine A. [1 ,2 ]
Silke, John [1 ,2 ]
Alexander, Warren S. [1 ,2 ]
Green, Douglas R. [3 ]
Strasser, Andreas [1 ,2 ]
机构：
[1] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia
[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3050, Australia
[3] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA
[4] Univ Hlth Network, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada
[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada
来源：
IMMUNITY | 2016年 / 45卷 / 03期
基金：
英国医学研究理事会;
关键词：
MIXED LINEAGE KINASE; NLRP3 INFLAMMASOME ACTIVATION; DOMAIN-LIKE PROTEIN; CELL-DEATH; LYMPHOPROLIFERATIVE SYNDROME; PROGRAMMED NECROSIS; CASPASE-8; TNF; NECROPTOSIS; CYTOKINE;
D O I：
10.1016/j.immuni.2016.07.016
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8(-/-)Mlkl(-/-) and Fadd(-/-) Mlkl(-/-) mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease, and thrombocytopenia. Thesemorbidities occurred more rapidly and with increased severity in Casp8(-/-)Mlkl(-/-) and Fadd(-/-) Mlkl(-/-) mice compared to Casp8(-/-) Ripk3(-/-)or Fadd(-/-) Ripk3(-/-) mice,respectively. These results demonstrate that MLKL is an essential effector of aberrant necroptosis in embryos caused by loss of Caspase-8 or FADD. Furthermore, they suggest that RIPK3 and/or MLKL may exert functions independently of necroptosis. It appears that non-necroptotic functions of RIPK3 contribute to the lymphadenopathy, autoimmunity, and excess cytokine production that occur when FADD or Caspase-8-mediated apoptosis is abrogated.
引用
收藏
页码：513 / 526
页数：14
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