肝星状细胞（HSC）在肝纤维化过程中被激活，分化为肌成纤维细胞并产生细胞外纤维基质。肝纤维化反应是通过 HSC 和巨噬细胞及其分泌产物之间的相互作用来协调的。 SOCS1 可以调节与肝纤维化有关的多种细胞因子和生长因子。在这里，我们研究了SOCS1在调节HSC激活中的作用。HSC中缺乏SOCS1的小鼠（Socs1ΔHSC）是通过Socs1fl/fl和LratCre小鼠杂交产生的。采用四氯化碳诱导肝纤维化，并通过天狼星红染色、羟脯氨酸含量和肌成纤维细胞免疫染色进行评估。通过 RT-qPCR 定量促纤维化因子、细胞因子、生长因子和趋化因子的基因表达。通过流式细胞术研究肝内白细胞亚群的表型和数量。评估了纤维化对二乙基亚硝胺诱导的肝细胞癌发展的影响。Socs1ΔHSC 小鼠比对照 Socs1fl/fl 小鼠出现更严重的肝纤维化，其特征是胶原沉积和肌成纤维细胞分化增加。 Socs1ΔHSC 小鼠在纤维化诱导后，肝脏中平滑肌肌动蛋白、胶原蛋白、基质金属蛋白酶、细胞因子、生长因子和趋化因子的表达显着增加。 Socs1ΔHSC 小鼠的纤维化肝脏显示炎症细胞浸润加剧，Ly6ChiCCR2 促炎巨噬细胞的比例和数量增加。该巨噬细胞群含有大量 CCR2 CX3CR1 细胞，表明向恢复性巨噬细胞的转变受损。暴露于二乙基亚硝胺后的纤维化诱导导致 Socs1ΔHSC 小鼠比 Socs1fl/fl 小鼠产生更多、更大的肝脏肿瘤结节。我们的研究结果表明 (i) HSC 中的 SOCS1 表达对于控制肝纤维化和肝细胞癌的发展至关重要， (ii) SOCS1 减弱 HSC 激活可调节肝纤维化过程中促炎性巨噬细胞的募集和分化。版权所有 © 2023 Kandhi、Yeganeh、Yoshimura、Menendez、Ramanathan 和 Ilangumaran。

Hepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation.Mice lacking SOCS1 in HSCs (Socs1ΔHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated.Socs1ΔHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1ΔHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1ΔHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1ΔHSC mice than in Socs1fl/fl mice.Our findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis.Copyright © 2023 Kandhi, Yeganeh, Yoshimura, Menendez, Ramanathan and Ilangumaran.