The JNK/P38 signalling pathway activated by testin protects the intestinal epithelial barrier against Crohn's disease-like colitis

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2024-09-04 DOI:10.1016/j.cbi.2024.111222

Xue Song , Xiaofeng Zhang , Min Zhang , Shengbao Liu , Nuo Zhang , Xinyue Liu , Bohan Li , Jing Li , Zhijun Geng , Lugen Zuo , Yueyue Wang , Lian Wang , Jianguo Hu

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引用次数: 0

Abstract

The unknown mechanism that controls intestinal barrier dysfunction in individuals with Crohn's disease (CD) plays a crucial role in the onset of intestinal inflammation. Testin, an intercellular linker protein, has the potential to protect epithelial barrier function. This study aimed to analyse the effects of Testin on CD-like colitis and explore the possible underlying mechanism. Colon samples from CD patients and trinitrobenzene-sulfonic acid (TNBS)-treated mice were collected to examine changes in Testin expression. To assess the therapeutic effects of Testin on CD-like colitis in mice, we examined the symptoms of enteritis, performed histological analysis, and evaluated intestinal barrier permeability. The ability of Testin to stabilize tight junction (TJ) proteins was investigated via immunofluorescence and western blotting. We conducted in vivo and in vitro experiments using colonic organoids and blocking techniques to explore how Testin safeguards the integrity of the intestinal barrier. Testin expression was downregulated in the colons of CD patients and TNBS-treated mice. Increasing Testin expression led to amelioration of colitis symptoms and reduced the production of inflammatory cytokines in the colons of TNBS-induced colitis model mice. Furthermore, increased Testin expression resulted in decreased depletion of TJ proteins (ZO-1 and Claudin-1) and promoted the effectiveness of the intestinal barrier in mice with TNBS-induced colon damage and in lipopolysaccharide (LPS)-stimulated colonic organoids. Elevated Testin levels inactivated the JNK/P38 signalling pathway, potentially contributing to the beneficial impact of Testin on the intestinal barrier. Testin can inhibit the loss of TJ proteins in CD mice by inactivating the JNK/P38 pathway. These findings help to clarify how Testin alleviates CD-like colitis in mice by protecting intestinal barrier function. These findings could lead to the use of a new treatment approach for CD in clinical practice.

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睾丸素激活的 JNK/P38 信号通路可保护肠上皮屏障免受克罗恩病样结肠炎的侵袭。

控制克罗恩病（CD）患者肠道屏障功能障碍的未知机制在肠道炎症的发生中起着至关重要的作用。睾丸素是一种细胞间连接蛋白，具有保护上皮屏障功能的潜力。本研究旨在分析睾丸素对类克氏结肠炎的影响，并探索其可能的内在机制。研究人员收集了 CD 患者和经三硝基苯磺酸（TNBS）处理的小鼠的结肠样本，以检测睾丸素表达的变化。为了评估睾丸素对小鼠类 CD 结肠炎的治疗效果，我们检查了肠炎的症状，进行了组织学分析，并评估了肠屏障的通透性。我们通过免疫荧光和 Western 印迹法研究了睾丸素稳定紧密连接（TJ）蛋白的能力。我们使用结肠器官组织和阻断技术进行了体内和体外实验，以探索睾丸素如何保护肠屏障的完整性。在 CD 患者和 TNBS 治疗小鼠的结肠中，睾丸素的表达下调。增加睾丸素的表达可改善TNBS诱导的结肠炎模型小鼠的结肠炎症状，并减少炎性细胞因子的产生。此外，在 TNBS 诱导的结肠损伤小鼠和脂多糖（LPS）刺激的结肠器官组织中，Testin 表达的增加导致 TJ 蛋白（ZO-1 和 claudin-1）消耗减少，并促进了肠道屏障的有效性。睾丸素水平升高会使 JNK/P38 信号通路失活，这可能是睾丸素对肠屏障产生有益影响的原因。睾丸素可通过使JNK/P38通路失活来抑制CD小鼠体内TJ蛋白的损失。这些发现有助于阐明睾丸素如何通过保护肠道屏障功能来缓解小鼠的CD样结肠炎。这些发现可为临床实践提供一种治疗 CD 的新方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.