Platelet c-type lectin-like receptor reduces cholestatic liver injury in mice.

Abstract Cholestatic liver injury leads to liver dysfunction. The available evidence suggests that platelets can either promote or reduce liver injury and fibrosis. We focused on the functions of the c-type lectin-like receptor (CLEC-2), a new special platelet receptor that binds with podoplanin activating platelets. We investigated the role of CLEC-2 and podoplanin in cholestatic liver injury. We injected mice intraperitoneally with weekly doses of anti-CLEC-2 antibody (2A2B10) to achieve effective CLEC-2 inhibition in their platelets. Next, we performed left and middle hepatic bile duct ligation (BDL) procedures and sacrificed mice a week later (2A2B10-BDL group). In addition, we prepared mice for control groups and compared relevant histological and laboratory variables among these groups. The inhibition of CLEC-2 resulted in increasing hepatocellular necrosis, hepatic inflammation, and liver fibrosis. In addition, podoplanin was strongly expressed in hepatic sinusoidal endothelial cells in BDL-treated mice. Moreover, in 2A2B10-BDL mice, the total plasma bile acid was significantly increased. In summary, podoplanin is expressed on hepatic sinusoidal endothelial cells upon BDL. Platelets bind with podoplanin via CLEC-2 and get activated. As a result, the total bile acid pool is decreased. Therefore, the CLEC-2-podoplanin interaction promotes liver protection and inhibits liver fibrosis after cholestatic liver injury.