Cutting Edge: RIP1 Kinase Activity Is Dispensable for Normal Development but Is a Key Regulator of Inflammation in SHARPIN-Deficient Mice

被引：311

作者：

Berger, Scott B. ^{[1
]}

Kasparcova, Viera ^{[1
]}

Hoffman, Sandy ^{[1
]}

Swift, Barb ^{[1
]}

Dare, Lauren ^{[1
]}

Schaeffer, Michelle ^{[1
]}

Capriotti, Carol ^{[1
]}

Cook, Michael ^{[1
]}

Finger, Joshua ^{[1
]}

Hughes-Earle, Angela ^{[2
]}

Harris, Philip A. ^{[1
]}

Kaiser, William J. ^{[3
]}

Mocarski, Edward S. ^{[3
]}

Bertin, John ^{[1
]}

Gough, Peter J. ^{[1
]}

机构：

[1] GlaxoSmithKline, Pattern Recognit Receptor Discovery Performance U, Immunoinflammat Therapeut Area, Collegeville, PA 19422 USA

[2] GlaxoSmithKline, Platform Technol Sci, Safety Assessment, Collegeville, PA 19422 USA

[3] Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Immunol & Microbiol, Atlanta, GA 30322 USA

来源：

JOURNAL OF IMMUNOLOGY | 2014年 / 192卷 / 12期

基金：

美国国家卫生研究院;

关键词：

LINEAR UBIQUITINATION; TNF-ALPHA; NECROSIS; DIE;

D O I：

10.4049/jimmunol.1400499

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：

RIP1 (RIPK1) kinase is a key regulator of TNF-induced NF-kappa B activation, apoptosis, and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. In this study, we generated RIP1 kinase-dead (Ripk1 (K45A)) mice and showed they are viable and healthy, indicating that the kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1(K45A) mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed them with SHARPIN-deficient cpdm mice, which develop severe skin and multiorgan inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1(K45A) mice with the cpdm strain protected against all cpdm-related pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.

引用

页码：5476 / 5480

页数：5

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