The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury.
Overdose acetaminophen (APAP) can result in severe liver injury, which is responsible for nearly half of drug-induced liver injury in western countries. Previous studies have found that there existed massive hepatocellular necrosis and severe inflammatory response in APAP-induced liver injury. However, the mechanistic linkage between necroptosis and NLRP3 inflammasome pathway in APAP-induced hepatotoxicity remains poorly understood. In order to investigate the relationship between inflammation and hepatocytes death in APAP hepatotoxicity, a time-course model for APAP hepatotoxicity in C57/BL6 mice was established by intraperitoneal (i.p) injection of 300 mg/kg APAP in this study. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in necroptosis and NF-κB-NLRP3 inflammasome signaling pathway were determined by immunoblot and immunofluorescence analysis. The results demonstrated that APAP overdose resulted in a severe liver injury. Furthermore, the expression of critical molecules in NLRP3 inflammasome and necroptosis pathways peaked at 12-24 h, and then was decreased gradually, which is consistent with the pattern of pathological injury induced by APAP. Our further investigation found that the level of IL-1β in mouse liver was closely correlated with the level of phosphorylated MLKL following exposure to APAP. Furthermore, inhibition of necroptosis with necrostatin-1 significantly suppressed the activation of NLRP3 inflammasome signaling. Taken together, our results highlighted that the cross-talk between necroptosis and NLRP3 inflammasome played a critical role for promoting APAP-induced liver injury. Inhibition of the interaction of inflammation and necroptosis by pharmaceutical methods may represent a promising therapeutic strategy for APAP-induced liver injury.
['Li|L|L|https://orcid.org/0000-0002-1722-5340', 'Shan|S|S|', 'Kang|K|K|', 'Zhang|C|C|', 'Kou|R|R|', 'Song|F|F|']
D000082:Acetaminophen D018712:Analgesics, Non-Narcotic D000818:Animals D056486:Chemical and Drug Induced Liver Injury D022781:Hepatocytes D058847:Inflammasomes D053583:Interleukin-1beta D008099:Liver D008297:Male D008810:Mice, Inbred C57BL D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D000079302:Necroptosis D011494:Protein Kinases D053422:Receptor-Interacting Protein Serine-Threonine Kinases
NLRP3 inflammasome acute liver injury Acetaminophen necroptosis