Role of Chemokine Receptors Ccr1 and Ccr5 in Acetaminophen-Induced Liver Injury in Mice

The molecular family of chemokines and their receptors are among the main regulators of directional leukocyte and T cell trafficking under homeostatic and inflammatory conditions. Recent studies showed that various immune responses are involved in the development of drug-induced hepatotoxicity. CCL5 is a very potent pro-inflammatory cytokine and exerts its actions by binding to three receptors (CCR1, CCR3, and CCR5) that is a major driver of inflammation and fibrosis in liver injury. In murine, CCR1 is expressed on neutrophils and is upregulated on neutrophils and inhibition of the migration of inflammatory cells into inflamed tissues. CCR5 is expressed on T cells, monocytes, and NK cells. In mice liver, CCR5 is expressed at high levels in lymphocytes. CCR1 and CCR5 are thought to mediate the migration of T cells and macrophages into inflamed tissues and involved in autoimmune and allergic diseases. CCR1 and CCR5 receptors are shown to be important in hepatic fibrosis with contributors to HSC–Kupffer cell interaction. Previous studies have showed that CCR5 antagonists have provided protection against HIV infection and CCR5-D32 mutation had a reduced liver inflammatory process in the HCV infective animals. Our group previous study also showed that hepatic ischemia and reperfusion injury was decreased in CCR5 deficiency mice. However, our preliminary data showed that APAP-induced acute hepatotoxicity is markly increase in the CCR5 knockout mice, and significant decrease in specific CCR1antagonist (J-113863) treated mice. The preliminary results suggest that both CCR1 and CCR5 have important effects through different cell populations in immune response, but the role of CCR1 and CCR5 in acetaminophen-induced liver injury pathophysiological processes is not clear. In this study, we will establish APAP-induced hepatotoxicity in vivo and ex vivo models for further understanding of CCR1 and CCR5 mechanisms and drug risk factors including their complex interactions, as well as for the new development of prevention and treatment in DILI (drug-induced liver injury).

Project ID:PC10108-1126
External Project ID:NSC101-2314-B182-082