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Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
Avlin B. Imaeda, … , Richard A. Flavell, Wajahat Z. Mehal
Avlin B. Imaeda, … , Richard A. Flavell, Wajahat Z. Mehal
Published January 26, 2009
Citation Information: J Clin Invest. 2009;119(2):305-314. https://doi.org/10.1172/JCI35958.
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Research Article

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome

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Abstract

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-1β and pro–IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1β and IL-18 from pro–IL-1β 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.

Authors

Avlin B. Imaeda, Azuma Watanabe, Muhammad A. Sohail, Shamail Mahmood, Mehdi Mohamadnejad, Fayyaz S. Sutterwala, Richard A. Flavell, Wajahat Z. Mehal

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Figure 1

APAP-mediated hepatotoxicity is dependent on Tlr9.

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APAP-mediated hepatotoxicity is dependent on Tlr9.
(A) Increase in total...
(A) Increase in total liver pro–IL-1β transcript in Tlr9+/+ mice 12 hours after APAP (500 mg/kg), which is significantly smaller in Tlr9–/– compared with Tlr9+/+ mice (*P < 0.01). (B) Significantly lower serum transaminase levels in Tlr9–/– compared with Tlr9+/+ mice 12 hours after a single toxic dose of APAP (*P < 0.01). (C) Less liver hemorrhage and necroinflammation in Tlr9–/– compared with Tlr9+/+ mice 12 hours after APAP (H&E staining; original magnification, ×20). (D) Kaplan-Meier survival curves for Tlr9+/+ and Tlr9–/– mice over 72 hours after a single toxic dose of APAP (Tlr9+/+: n = 15, Tlr9–/–: n = 17, P < 0.04). Error bars indicate 1 SD. Ctrl, control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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