Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.
Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.
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DOI：
10.1038/cddis.2015.126
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发表时间：
2015-05-07
影响因子：
9
通讯作者：
Miller G
中科院分区：
文献类型：
--
作者：
Deutsch M;Graffeo CS;Rokosh R;Pansari M;Ochi A;Levie EM;Van Heerden E;Tippens DM;Greco S;Barilla R;Tomkötter L;Zambirinis CP;Avanzi N;Gulati R;Pachter HL;Torres-Hernandez A;Eisenthal A;Daley D;Miller G
坏死性凋亡是最近描述的一种不依赖于 Caspase 8 的细胞死亡方法，表示有组织的细胞坏死。 RIP1 和 RIP3 在介导急性肝损伤引起的肝细胞死亡中的作用尚未完全确定。通过在不同的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。阻断坏死性凋亡对疾病结果有不同的影响，具体取决于肝损伤的确切病因和目标坏死体的成分。在ConA诱导的自身免疫性肝炎中，RIP3缺失具有保护作用，而RIP1抑制会加剧疾病，加速动物死亡，并与肝细胞凋亡增加相关。相反，在对乙酰氨基酚介导的肝损伤中，阻断 RIP1 或 RIP3 具有保护作用，并且与较低的 NLRP3 炎性体激活相关。我们的工作强调了这样一个事实：不同模式的急性肝损伤对 RIP1 和 RIP3 有不同的要求；此外，在单一损伤模型中，RIP1和RIP3阻断可能对组织损伤产生截然相反的影响，这表明必须单独考虑对坏死体不同成分的干扰。
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.