Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury
Toxicology and Applied Pharmacology
Acetaminophen hepatotoxicity; Damage associated molecular patterns; High mobility group box protein; Inflammasome; Neutrophils; Sterile inflammation
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-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β 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 C57Bl/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-1β 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. © 2011 Elsevier Inc.
Williams, C., Antoine, D., Shaw, P., Benson, C., Farhood, A., Williams, D., Kanneganti, T., Park, B., & Jaeschke, H. (2011). Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. Toxicology and Applied Pharmacology, 252 (3). http://dx.doi.org/10.1016/j.taap.2011.03.001