Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL
Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL
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DOI：
10.1016/j.bbadis.2019.165583
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发表时间：
2020-01-01
影响因子：
6.2
通讯作者：
Wan, Xiaochun
中科院分区：
文献类型：
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作者：
Chen, Qian;Yan, Dehong;Wan, Xiaochun
对乙酰氨基酚（APAP）是世界范围内最常用的药物之一，APAP引起的肝损伤是发达国家急性肝衰竭的最常见原因。然而，APAP 引起的肝毒性的机制尚不清楚，并且该疾病的治疗选择非常有限。在这里，我们证明 TRAIL（肿瘤坏死因子相关凋亡诱导配体）是 APAP 诱导的小鼠肝损伤的主要介质，其阻断可显着改善肝衰竭。在APAP治疗的小鼠中，TRAIL主要由CD11b(+)Gr1(+)中性粒细胞在肝脏、脾脏和外周血中表达。血液中可溶性TRAIL浓度以及脾脏和肝脏中TRAIL(+)白细胞的频率与肝损伤的严重程度呈正相关。 APAP 可能通过其转录因子 CHOP（C/EBP 同源蛋白）上调 TRAIL 受体 DR5（死亡受体 5）的表达，使肝细胞对 TRAIL 诱导的细胞凋亡敏感。重要的是，用可溶性 DR5-Fc 融合蛋白 (sDR5-Fc) 阻断 TRAIL 可显着减轻 APAP 诱导的肝损伤、白细胞的肝脏浸润、炎症细胞因子的水平和小鼠的死亡率。当与 N-乙酰半胱氨酸一起给药时，sDR5-Fc 进一步防止 APAP 诱导的急性肝损伤。因此，TRAIL-DR5信号通路在APAP诱导的肝脏炎症和衰竭中发挥着关键作用，其阻断代表了治疗肝脏疾病的有效新策略。
Acetaminophen (APAP) is one of the most commonly used drugs worldwide, and APAP-induced liver injury is the most frequent cause of acute liver failure in developed countries. However, the mechanisms of APAP-induced hepatotoxicity are not well understood, and treatment options for the disorder are very limited. Here, we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a major mediator of APAP-induced liver injury in mice, and its blockade markedly ameliorates the liver failure. In APAP-treated mice, TRAIL was expressed in the liver, spleen, and peripheral blood primarily by CD11b(+)Gr1(+) neutrophils. The concentration of soluble TRAIL in the blood, and the frequencies of TRAIL(+) leukocytes in the spleen and liver positively correlated with the severity of liver injury. APAP sensitized hepatocytes to TRAIL-induced apoptosis by upregulating the expression of the TRAIL receptor DR5 (death receptor 5), presumably through its transcription factor CHOP (C/EBP homologous protein). Importantly, blocking TRAIL with a soluble DR5-Fc fusion protein (sDR5-Fc) significantly attenuated APAP-induced liver injury, the hepatic infiltration of leukocytes, the levels of inflammatory cytokines, and the mortality of mice. When administered alongside N-acetylcysteine, sDR5-Fc further protected against APAP-induced acute liver injury. Thus, the TRAIL-DR5 signaling pathway plays a key role in APAP-induced liver inflammation and failure, and its blockade represents an effective new strategy to treat the liver disease.