Toll 样受体 9 (Tlr9) 是一种病原体识别受体，可检测病原体和受损宿主细胞的未甲基化 DNA 衍生物。因此，它是先天免疫的重要调节剂。在此，我们研究了 Tlr9 在慢性肝病中肝细胞癌纤维形成和进展中的作用。我们用 DEN/CCl4 治疗 Tlr9 (Tlr9-/-) 组成型缺失的小鼠 24 周。作为第二个模型，我们使用肝细胞特异性 Nemo 敲除 (NemoΔhepa) 小鼠并生成双敲除 (NemoΔhepaTlr9-/-) 动物。我们表明 Tlr9 在肝脏中主要在 Kupffer 细胞中表达，表明 Tlr9 在细胞间质中发挥关键作用肝损伤期间的沟通。 Tlr9 缺失导致肝纤维化和肿瘤负荷减轻。我们观察到两种模型中肝星状细胞活化下调，从而导致胶原蛋白产生减少。 Tlr9 缺失与肝细胞凋亡减少和代偿性增殖相关，调节肝癌发生的起始和进展。这些发现伴随着干扰素-β 的减少和具有抗肿瘤作用的趋化因子的增加。我们的数据将 Tlr9 定义为参与纤维生成的重要受体，而且还参与慢性肝病期间肝细胞癌的发生和进展。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Toll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important modulator of innate immunity. Here we investigated the role of Tlr9 in fibrogenesis and progression of hepatocellular carcinoma in chronic liver disease.We treated mice with a constitutive deletion of Tlr9 (Tlr9-/-) with DEN/CCl4 for 24 weeks. As a second model, we used hepatocyte-specific Nemo knockout (NemoΔhepa) mice and generated double knockout (NemoΔhepaTlr9-/-) animals.We show that Tlr9 is in the liver primarily expressed in Kupffer cells, suggesting a key role of Tlr9 in intercellular communication during hepatic injury. Tlr9 deletion resulted in reduced liver fibrosis as well as tumor burden. We observed down-regulation of hepatic stellate cell activation and consequently decreased collagen production in both models. Tlr9 deletion was associated with decreased apoptosis and compensatory proliferation of hepatocytes, modulating the initiation and progression of hepatocarcinogenesis. These findings were accompanied by a decrease in interferon-β and an increase in chemokines having an anti-tumoral effect.Our data define Tlr9 as an important receptor involved in fibrogenesis, but also in the initiation and progression of hepatocellular carcinoma during chronic liver diseases.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.