Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice.
Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice.
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DOI：
10.4049/jimmunol.1400499
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Gough PJ
中科院分区：
文献类型：
--
作者：
Berger SB;Kasparcova V;Hoffman S;Swift B;Dare L;Schaeffer M;Capriotti C;Cook M;Finger J;Hughes-Earle A;Harris PA;Kaiser WJ;Mocarski ES;Bertin J;Gough PJ
RIP 1激酶是TNF诱导的NFκB活化、凋亡和坏死性凋亡的关键调节因子。在发育和TNF依赖性炎症过程中，RIP 1激酶活性和支架功能在体内的平衡被RIP 1缺陷小鼠的围产期致死率所阻碍。在这里，我们产生了RIP 1激酶死亡（Ripk 1 K45 A）小鼠，并显示它们是可行的和健康的，表明RIP 1的激酶活性，而不是其支架功能，是可行的和稳态。在验证Ripk 1 K45 A小鼠在体外和体内对坏死性凋亡刺激具有特异性保护后，我们将这些小鼠与SHARPIN缺陷型cpdm小鼠杂交，后者发生严重的皮肤和多器官炎症，推测其由TNF依赖性凋亡和/或坏死性凋亡介导。值得注意的是，将Ripk 1 K45 A小鼠与cpdm品系杂交，可防止所有cpdm相关的病理学。总之，这些数据表明，RIP 1激酶代表了TNF驱动的炎症性疾病的有吸引力的治疗靶点。
RIP1 kinase is a key regulator of TNF-induced NFκB 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. Here we generated RIP1 kinase-dead (Ripk1K45A) mice and showed they are viable and healthy, indicating that kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1K45A mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed these mice to SHARPIN-deficient cpdm mice, which develop severe skin and multi-organ inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1K45A mice to 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.
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