Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

C. David Williams, Daniel J. Antoine, Patrick J. Shaw, Craig Benson, Anwar Farhood, Dominic P. Williams, Thirumala-Devi Kanneganti, B. Kevin Park, Hartmut Jaeschke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1 beta (IL-1 beta), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1 beta is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57BI/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1 beta and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. (C) 2011 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)289-297
Number of pages9
JournalToxicology and Applied Pharmacology
Volume252
Issue number3
DOIs
Publication statusPublished - 1 May 2011

Keywords

  • Acetaminophen hepatotoxicity
  • Sterile inflammation
  • Inflammasome
  • Damage associated molecular patterns
  • High mobility group box protein
  • Neutrophils
  • CHROMATIN PROTEIN HMGB1
  • INDUCED HEPATOTOXICITY
  • OXIDANT STRESS
  • ISCHEMIA-REPERFUSION
  • HEPATIC ISCHEMIA
  • NECROTIC CELLS
  • MICE
  • MECHANISMS
  • APOPTOSIS
  • NEUTROPHILS

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