Cristina Bárcena1, Milica Stefanovic1, Anna Tutusaus1, Leonel Joannas2, Anghara Menéndez3, Carmen García-Ruiz1, Pau Sancho-Bru4, Montserrat Marí1, Joan Caballeria4, Carla V Rothlin2, José C Fernández-Checa5, Pablo García de Frutos6, Albert Morales7. 1. Liver Unit, Hospital Clinic, IDIBAPS-CIBEK, CIBEREHD, Barcelona, Catalonia, Spain; Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain. 2. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. 3. Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain. 4. Liver Unit, Hospital Clinic, IDIBAPS-CIBEK, CIBEREHD, Barcelona, Catalonia, Spain. 5. Liver Unit, Hospital Clinic, IDIBAPS-CIBEK, CIBEREHD, Barcelona, Catalonia, Spain; Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain; Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 6. Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain. Electronic address: pablo.garcia@iibb.csic.es. 7. Liver Unit, Hospital Clinic, IDIBAPS-CIBEK, CIBEREHD, Barcelona, Catalonia, Spain; Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain. Electronic address: amorales@clinic.ub.es.
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 WT 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 WT 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(-/-) 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.
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 WT 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 WT 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(-/-) 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 HCVpatients, 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.
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