Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice

Abstract

Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. While Oncostatin M (OSM) has been reported to play crucial roles for the recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury is yet to be elucidated. Here we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during chronic liver injury. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis after hepatitis. In a primary co-culture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors such as TGF-ß and PDGF in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. FACS analyses using OSM-HTVi and OSM KO mice have revealed that bone marrow derived monocyte/macrophage are responsive to OSM for pro-fibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. Conclusion: OSM plays a crucial role in liver fibrosis by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for liver fibrosis. This article is protected by copyright. All rights reserved.

http://ift.tt/2hxn37y