CCL25是D-Gal/LPS诱导的急性肝衰竭的发病机制之一。

IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Journal of Gastroenterology and Hepatology Pub Date : 2024-09-04 DOI:10.1111/jgh.16732
Fei Sun, Jingwei Wang, Xiangfen Ji, Zhenli Wang, Shuai Gao, Kai Wang
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引用次数: 0

摘要

背景和目的:急性肝衰竭(ALF)是一种严重肝功能异常的致命性临床综合征。趋化因子通过招募和激活免疫细胞促进肝脏疾病的发生。我们旨在研究 C-C 趋化因子配体 25(CCL25)在 ALF 中的作用:方法:通过肝脏苏木精和伊红染色以及血清转氨酶和细胞因子测定,评估了由 D-半乳糖胺/脂多糖诱导的 ALF 小鼠模型。血清中CCL25的表达通过酶联免疫吸附试验进行分析,肝脏中CCL25的表达通过免疫组化染色和Western印迹进行分析。肝脏中表达C-C趋化因子受体9(CCR9)的细胞是通过免疫荧光染色确定的。在体内评估了抗CCL25对ALF的影响。研究了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。NF-κB 的活化通过 Western 印迹进行评估,p65 的核转位通过细胞免疫荧光进行检测:结果:ALF小鼠表现出严重的组织学损伤,血清中转氨酶和炎症细胞因子水平较高。体内观察到 CCL25 和 NF-κB 活化升高。CCR9在ALF小鼠肝脏的巨噬细胞中表达。抗CCL25治疗后,ALF受到抑制,NF-κB受到明显抑制。在体外,CCL25诱导RAW264.7巨噬细胞强烈迁移并释放细胞因子,而抗CCL25和BMS-345541可消除这些作用。此外,抗 CCL25 和 BMS-345541 还能抑制 CCL25 诱导的 NF-κB 激活和 p65 核转位:结论:CCL25 通过激活 NF-κB 信号诱导巨噬细胞介导的炎症,从而促进 ALF 的发展。
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CCL25 contributes to the pathogenesis of D-Gal/LPS-induced acute liver failure.

Background and aim: 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.

Methods: 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.

Results: 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.

Conclusion: CCL25 contributes to ALF development by inducing macrophage-mediated inflammation via activation of the NF-κB signaling.

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来源期刊
CiteScore
7.90
自引率
2.40%
发文量
326
审稿时长
2.3 months
期刊介绍: Journal of Gastroenterology and Hepatology is produced 12 times per year and publishes peer-reviewed original papers, reviews and editorials concerned with clinical practice and research in the fields of hepatology, gastroenterology and endoscopy. Papers cover the medical, radiological, pathological, biochemical, physiological and historical aspects of the subject areas. All submitted papers are reviewed by at least two referees expert in the field of the submitted paper.
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