Sun Fei, Wang Jingwei, Ji Xiangfen, Wang Zhenli, Gao Shuai, Wang Kai
Department of Hepatology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China.
Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China.
J Gastroenterol Hepatol. 2024 Dec;39(12):2880-2891. doi: 10.1111/jgh.16732. Epub 2024 Sep 4.
Acute liver failure (ALF) is a fatal clinical syndrome of severe hepatic dysfunction. Chemokines promote liver diseases by recruiting and activating immune cells. We aimed to investigate the role of C-C chemokine ligand 25 (CCL25) in ALF.
An ALF mouse model induced by D-galactosamine/lipopolysaccharide was evaluated through liver hematoxylin and eosin staining and serum transaminase and cytokine measurement. CCL25 expression in serum was analyzed by ELISA and in liver by immunohistochemical staining and western blot. C-C chemokine receptor 9 (CCR9)-expressing cells in the liver were identified by immunofluorescence staining. The effects of anti-CCL25 on ALF were evaluated in vivo. Cytokine expression and migration of CCL25-stimulated RAW264.7 macrophages were studied. We also investigated the role of anti-CCL25 and BMS-345541, an NF-κB signaling inhibitor, in vitro. NF-κB activation was assessed via western blot, and p65 nuclear translocation was detected using cellular immunofluorescence.
ALF mice showed severe histological damage and high serum levels of aminotransferase and inflammatory cytokines. Elevated CCL25 and NF-κB activation was observed in vivo. CCR9 was expressed on macrophages in ALF mouse liver. ALF was suppressed after anti-CCL25 treatment, with significant NF-κB inhibition. In vitro, CCL25 induced strong migration and cytokine release in RAW264.7 macrophages, which were eliminated by anti-CCL25 and BMS-345541. Furthermore, the NF-κB activation and p65 nuclear translocation induced by CCL25 were also inhibited by anti-CCL25 and BMS-345541.
CCL25 contributes to ALF development by inducing macrophage-mediated inflammation via activation of the NF-κB signaling.
急性肝衰竭（ALF）是一种严重肝功能障碍的致命临床综合征。趋化因子通过募集和激活免疫细胞促进肝脏疾病。我们旨在研究C-C趋化因子配体25（CCL25）在急性肝衰竭中的作用。
通过肝苏木精-伊红染色以及血清转氨酶和细胞因子检测，对由D-半乳糖胺/脂多糖诱导的急性肝衰竭小鼠模型进行评估。采用酶联免疫吸附测定（ELISA）分析血清中CCL25的表达，通过免疫组织化学染色和蛋白质免疫印迹法检测肝脏中CCL25的表达。通过免疫荧光染色鉴定肝脏中表达C-C趋化因子受体9（CCR9）的细胞。在体内评估抗CCL25对急性肝衰竭的影响。研究CCL25刺激的RAW264.7巨噬细胞的细胞因子表达和迁移。我们还在体外研究了抗CCL25和NF-κB信号抑制剂BMS-345541的作用。通过蛋白质免疫印迹法评估NF-κB的激活，并使用细胞免疫荧光检测p65核转位。
急性肝衰竭小鼠表现出严重的组织学损伤以及血清转氨酶和炎性细胞因子水平升高。在体内观察到CCL25升高和NF-κB激活。CCR9在急性肝衰竭小鼠肝脏的巨噬细胞上表达。抗CCL25治疗后急性肝衰竭得到抑制，NF-κB受到显著抑制。在体外，CCL25诱导RAW264.7巨噬细胞强烈迁移和细胞因子释放，而抗CCL25和BMS-345541可消除这些作用。此外，抗CCL25和BMS-345541也抑制了CCL25诱导的NF-κB激活和p65核转位。
CCL25通过激活NF-κB信号诱导巨噬细胞介导的炎症，从而促进急性肝衰竭的发展。
