CX3CL1 promotes macrophage accumulation and stellate cell activation in BDL‐induced hepatic fibrogenesis

Hepatic fibrosis represents an important feature of a number of chronic liver pathologies. Fractalkine (CX 3 CL 1 ) and its only known receptor CX 3 CR 1 are expressed in a number of chronic liver diseases including primary biliary cirrhosis and may play an important role in the inflammatory response. The purpose of the current study was to determine the importance of CX 3 CL 1 in the cholestatic liver using a well‐established model of bile duct ligation in the mouse. Wild type mice subjected to BDL showed significant enhancement in both CX 3 CL 1 and CX 3 CR 1 expression at 14 and 21 days post‐ligation in conjunction with increased liver injury, macrophage recruitment, stellate cell activation, and collagen deposition. In the absence of CX 3 CR 1 , significant reductions in stellate cell activation (50% reduction), macrophage recruitment (47.1% reduction), and collagen deposition (38.4% reduction) were observed in the absence of major changes in liver enzyme release. Further analysis in vitro revealed the ability of CX 3 CL 1 to stimulate primary stellate cell collagen production (20‐fold increase) and Kupffer cell migration (2‐fold increase). Together, these data demonstrate the importance of CX 3 CL 1 ‐CX 3 CR 1 interactions in the progression of cholestasis‐induced hepatic fibrosis. These studies were supported in part by grants from the NIAAA (AA016563) and the Alcoholic Beverage Medical Research Foundation.