ACTIVIN B PROMOTES HEPATIC FIBROGENESIS

Activin B, a TGFβ ligand, is associated with liver inflammatory response. We aimed to investigate whether it modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute liver injury and liver fibrosis models. Activin B, activin A, or both was immunologically neutralized in progressive or established carbon tetrachloride-induced mouse liver fibrosis. The direct effects of activin B and A on hepatocytes, macrophages, and hepatic stellate cells (HSCs) were evaluated in vitro. In human patients, increased activin B is associated with liver fibrosis irrespective of the etiologies. In mice, activin B exhibited persistent elevation in liver and circulation following the onset of liver injury, whereas activin A displayed transient increases. Neutralizing activin B largely prevented and remarkably regressed liver fibrosis, which was augmented by co-neutralizing activin A in mice. Mechanistically, activin B promoted hepatocyte injury, activated macrophages to release cytokines, and induced a pro-fibrotic expression profile and septa formation in HSCs, which were magnified by activin A. Furthermore, activin B and A interdependently activated the CXCL1/iNOS pathway in macrophages and additively upregulated CTGF transcript in HSCs in vitro. Consistently, the expression of these genes was prohibited by neutralizing either one of these two ligands in injured livers. Activin B potently drives the initiation and progression of liver fibrogenesis. It additively or interdependently cooperates with activin A, directly acts on multiple liver cell populations, and induces liver fibrogenesis. Antagonizing activin B or both activins B and A prevents and regresses liver fibrosis in mouse CCl₄ model, inspiring the development of a novel therapy of chronic liver diseases.