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

被引：226

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：

071005 [微生物学]; 100108 [医学免疫学];

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

页码：513 / 526

页数：14

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