Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
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DOI：
10.1172/jci35958
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发表时间：
2009-02-01
影响因子：
15.9
通讯作者：
Mehall, Wajahat Z.
中科院分区：
文献类型：
--
作者：
Imaeda, Avlin B.;Watanabe, Azuma;Mehall, Wajahat Z.
肝细胞死亡导致无菌炎症反应，其放大初始损伤并增加整体组织损伤。这种类型的损伤的一个重要例子是对乙酰氨基酚诱导的肝损伤，其中初始毒性损伤之后是先天免疫激活。使用缺乏Tlr 9和炎性体组分Nalp 3（NACHT、LRR和含pyrin结构域的蛋白3）、ASC（包含CARD的骨化相关斑点样蛋白）和半胱天冬酶-1的小鼠，我们已经确定了Tlr 9和Nalp 3炎性体在对乙酰氨基酚诱导的肝损伤中的非冗余作用。我们已经表明，对乙酰氨基酚治疗导致肝细胞死亡，并且从凋亡肝细胞释放的游离DNA激活Tlr 9。这触发了信号级联，增加了窦状隙内皮细胞中编码pro-IL-1 β和pro-IL-18的基因的转录。通过激活半胱天冬酶-1（负责分别从pro-IL-1 β和pro-IL-18产生成熟IL-1 β和IL-18的酶），Nalp 3炎性体在对乙酰氨基酚诱导的肝损伤后促炎细胞因子激活的第二步中发挥关键作用。TLR 9拮抗剂和阿司匹林降低了对乙酰氨基酚肝毒性的死亡率。阿司匹林对乙酰氨基酚诱导的肝损伤的保护作用是由于下调促炎细胞因子，而不是抑制血小板脱颗粒或考克斯-1抑制。总之，我们已经确定了对乙酰氨基酚诱导的肝毒性和一些潜在的治疗方法的2信号要求（Tlr 9和Nalp 3炎性体）。
Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1 beta and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1 beta and IL-18 from pro-IL-1 beta and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.