Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Abstract

Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.

Hepatic stellate cells as key target in liver fibrosis

“…Serum Gas6 level is increased as alcoholic liver disease or chronic hepatitis C progresses [202]. Axl knockout as well as inhibition by BGB324 result in attenuated HSC activation and reduced fibrosis in CCl 4 mice.…”

Role of Tyro3, Axl, and Mer Receptors and Their Ligands (Gas6, and Protein S) in Patients with Hepatocellular Carcinoma

“…On the other hand, Gas6 plasma level increases in parallel to liver fibrosis in chronic liver diseases (CH and LC) progression [35]. Liver fibrosis in the development of liver cirrhosis with persistent inflammation may lead to a favorable microenvironment for cancer development.…”

Gas6 /TAM system: physiological insights and diseases

“…The role of Gas6/Axl pathway in liver fibrosis is by participating in the activation of HSC. Therefore, small molecule inhibitors against Axl, that effectively eliminate HSC activation and reduce experimental fibrosis progression, may be interesting therapeutic tool for future clinical trials [42].…”