Liver fibrosis (LF) caused by chronic inflammation is characterized by excess deposition of abnormal extracellular matrix (ECM). Unchecked LF leads to cirrhosis and hepatocellular carcinoma. Previously we have shown that mice lacking SOCS1 show increased LF, accompanied by activation of hepatic stellate cells (HSC), a key player in hepatic fibrogenesis. Here we investigated whether the loss of SOCS1 in HSC alone is sufficient to promote LF, or SOCS1 deficiency in hepatocytes and macrophages are also necessary for LF.
We generated mice lacking SOCS1 in HSC (SOCS1ΔHSC; Socs1fl/flLratCre), hepatocytes (SOCS1ΔHep; Socs1fl/flAlbCre) or macrophages (SOCS1ΔMφ; Socs1fl/flLys-MCre). Control (Socs1fl/fl) and tissue-specific SOCS1 deficient mice were treated with carbon tetrachloride (CCl4). Liver damage and fibrosis were evaluated by serum ALT, histopathology and liver hydroxyproline content. Upregulation of inflammatory and fibrogenic cytokines and ECM components, and modulation of ECM remodeling enzymes were assessed by qRT-PCR and western blot.
Following exposure to CCl4 SOCS1ΔHSC mice showed increased LF compared to control mice, associated with increased collagen deposition and loss of hepatic lobular structure. SOCS1ΔHSC livers showed increased expression of genes coding for smooth muscle actin, collagen alpha 1 and matrix metalloproteases, and altered expression of genes encoding tissue inhibitor of metalloproteinases (Sma, Cola1, Mmp3, Mmp9, Timp1, Timp2 and Timp4). SOCS1ΔMφ mice also developed severe LF. The livers of SOCS1ΔHSC and SOCS1ΔMφ mice displayed increased mononuclear cell infiltration.
Our findings indicate that SOCS1 is an important endogenous regulator of HSC activation during hepatic fibrogenic response. However, SOCS1 deficiency in Mφ alone is sufficient to deregulate HSC activation. Hence, SOCS1 exerts its anti-fibrotic functions in multiple cellular compartments of the liver and is possibly involved in regulating the crosstalk between HSC and immune cells during hepatic fibrogenic response.