Deutsch M, Graffeo C S, Rokosh R, Pansari M, Ochi A, Levie E M, Van Heerden E, Tippens D M, Greco S, Barilla R, Tomkötter L, Zambirinis C P, Avanzi N, Gulati R, Pachter H L, Torres-Hernandez A, Eisenthal A, Daley D, Miller G
S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
Cell Death Dis. 2015 May 7;6(5):e1759. doi: 10.1038/cddis.2015.126.
Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.
坏死性凋亡是一种最近被描述的不依赖于半胱天冬酶8的细胞死亡方式，代表有组织的细胞坏死。RIP1和RIP3在介导急性肝损伤导致的肝细胞死亡中的作用尚未完全明确。通过在多种急性肝损伤小鼠模型中分别靶向RIP1和RIP3，研究了坏死性凋亡阻断的效果。根据肝损伤的确切病因和靶向坏死小体的成分，坏死性凋亡的阻断对疾病结局有不同的影响。在刀豆蛋白A诱导的自身免疫性肝炎中，RIP3缺失具有保护作用，而RIP1抑制则加剧了疾病，加速了动物死亡，并与肝细胞凋亡增加有关。相反，在对乙酰氨基酚介导的肝损伤中，阻断RIP1或RIP3均具有保护作用，并与较低的NLRP3炎性小体激活有关。我们的研究突出了这样一个事实，即不同模式的急性肝损伤对RIP1和RIP3有不同的需求；此外，在单一损伤模型中，RIP1和RIP3阻断对组织损伤可能产生截然相反的影响，这表明必须分别考虑对坏死小体不同成分的干扰。
