Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
J Hepatol. 2021 Mar;74(3):511-521. doi: 10.1016/j.jhep.2020.09.033. Epub 2020 Oct 8.
BACKGROUND & AIMS: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH.
Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9 mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH.
Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9 mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9CD11b inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9 mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine.
These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH.
Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis.
非酒精性脂肪性肝炎（NASH）患者数量在全球范围内呈上升趋势。最近，特定趋化因子受体已成为 NASH 治疗靶点的研究热点。本研究首次探讨了 C-C 趋化因子受体 9（CCR9）/C-C 趋化因子配体 25（CCL25）轴的作用，并揭示了其在 NASH 中的治疗潜力。
招募经肝活检证实的非酒精性肝病（NAFLD）患者，检测其血清和肝脏趋化因子表达。此外，野生型（WT）和 Ccr9 小鼠用高脂肪高胆固醇（HFHC）饮食喂养 24 周，建立 NASH 模型。
与健康志愿者相比，NASH 患者血清 CCL25 及肝脏 CCR9 和 CCL25 表达水平升高。此外，CCr9 小鼠在血清学和组织学上均能防止 HFHC 饮食诱导的 NASH 进展。流式细胞术和免疫组织化学分析显示，CCR9+CD11b 炎性巨噬细胞在 HFHC 饮食喂养小鼠的炎症性肝脏中聚集，而 Ccr9 小鼠中的数量减少。与人类 NASH 肝脏一样，CCR9 也在 NASH 小鼠的肝星状细胞（HSCs）上表达，而 CCR9 缺陷型 HSCs 在体外表现出较低的纤维化潜能。CCR9 拮抗剂的给药阻碍了 NASH 小鼠的进一步纤维化进展，支持其在临床上的应用。最后，我们发现 CCR9 阻断可减轻 HF 饮食喂养的注射二乙基亚硝胺的小鼠中 NAFLD 相关肝细胞癌的发展。
这些结果突出了 CCR9/CCL25 轴在小鼠 NASH 模型中对巨噬细胞募集和纤维化形成的作用，为 NASH 的治疗策略提供了新的见解。
本文表明，涉及受体（CCR9）及其配体（CCL25）的特定趋化因子轴有助于人类和小鼠的非酒精性脂肪性肝炎和癌发生的进展。此外，用 CCR9 拮抗剂治疗可改善肝炎的发展，并有望治疗非酒精性脂肪性肝炎患者。
