RIPK1调节RIPK3-MLKL驱动的全身炎症和紧急血液形成
James A Rickard1, Joanne A O'Donnell1, Joseph M Evans2
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
Cell
|May 13, 2014
概括
缺乏RIPK1的小鼠死于炎症,但阻断亡可以防止这种情况. 通常情况下,RIPK1通过抑制亡来限制炎症,这表明它在控制炎症反应方面发挥了新的作用.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 受体相互作用蛋白激酶1 (RIPK1) 在TNFRSF和TLR信号传递中至关重要,调节细胞存活,炎症,亡和亡.
- 根据caspase-8的活性,RIPK1在促进生存和执行细胞死亡途径 (亡或亡) 中的双重作用是复杂的.
- 在Ripk1(-/-) 小鼠中,新生儿死亡率表明它在早期发育和炎症控制中起着关键作用.
研究的目的:
- 研究RIPK1在新生儿系统性炎症和血液形成中的精确作用.
- 阐明RIPK1调节炎症和细胞死亡途径的机制.
- 为了确定RIPK1在限制炎症的功能是否取决于亡或亡.
主要方法:
- 对各种淘汰赛小鼠模型 (Ripk1(-/-),Ripk3(-/-),Mlkl(-/-),Casp8(-/-),Myd88(-/-) 的生成和分析.
- 评估新生儿死亡率,全身炎症,紧急血液形成和细胞因子释放 (IL-33).
- 利用TNF阻断和Tnfr1缺陷来剖析信号通路.
主要成果:
- Ripk1(-/-) 小鼠表现出系统性炎症,并在出生时死亡,在紧急血液形成中存在缺陷.
- 阻断TNF部分挽救了血液形成,但Tnfr1缺乏不能防止Ripk1的炎症.
- 删除Ripk3或Mlkl,但不删除Casp8,可以防止IL-33的释放,并减少依赖Myd88的炎症,从而挽救新生儿死亡率.
- 组合Ripk1(-/-)Ripk3(-/-)Casp8(-/-) 小鼠在断奶后存活下来,这表明RIPK1在限制死驱动的炎症方面发挥了关键作用.
结论:
- 通过抑制亡,RIPK1在预防新生儿死亡方面发挥着至关重要的作用.
- RIPK1的功能是限制炎症,与其在促进炎症信号传递方面的已知作用相反.
- 这项研究揭示了一种新的机制,其中RIPK1起到了关键的作用,抑制了亡和相关的炎症.
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