Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice.

Abstract

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. APAP can cause extensive hepatocellular necrosis, which triggers an inflammatory response involving neutrophil and monocyte recruitment. Particularly the role of neutrophils in the injury mechanism of APAP hepatotoxicity has been highly controversial. Thus, the objective of the current study was to assess whether a potential contribution of neutrophils was dependent on the APAP dose and the sex of the animals. Male and female C57BL/6J mice were treated with 300 or 600mg/kg APAP and the injury and inflammatory cell recruitment was evaluated between 6 and 48h. In both male and female mice, ALT plasma levels and the areas of necrosis peaked at 12-24h after both doses with more severe injury at the higher dose. In addition, Ly6g-positive neutrophils started to accumulate in the liver at 6h and peaked at 6-12h after 300mg/kg and 12-24h after 600mg/kg for both sexes; however, the absolute numbers of hepatic neutrophils in the liver were significantly higher after the 600mg/kg dose. Neutrophil infiltration correlated with mRNA levels of the neutrophil chemoattractant Cxcl2 in the liver. Treating mice with an anti-Cxcl2 antibody at 2h after APAP significantly reduced neutrophil accumulation at 24h after both doses and in both sexes. However, the injury was significantly reduced only after the high overdose. Thus, neutrophils, recruited through Cxcl2, have no effect on APAP-induced liver injury after 300mg/kg but aggravate the injury only after severe overdoses.