Overdose of
acetaminophen (
APAP) causes
necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to
APAP-induced hepatotoxicity. Interaction between
RANTES and its receptor
C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of
inflammation. In this study, we examined effects of CCR5 deficiency on
APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received
intraperitoneal injection of
APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal
APAP caused the hepatocytic
necrosis, as evidenced by
hematoxylin and
eosin staining and an increase in
alanine transaminase and
aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in
cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in
APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of
gadolinium chloride significantly blocked
APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to
APAP-mediated hepatocytic death and CCR5 gene deletion protects from
APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of
APAP.