Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and Ulcerative colitis (UC) have a complex and multifactorial pathogenesis which is incompletely understood. A typical feature closely associated with clinical symptoms is impaired intestinal epithelial barrier function. Mounting evidence suggests that desmosomes, which together with tight junctions (TJ) and adherens junctions (AJ) form the intestinal epithelial barrier, play a distinct role in IBD pathogenesis. This is based on the finding that desmoglein (Dsg) 2, a cadherin‐type adhesion molecule of desmosomes, is required for maintenance of intestinal barrier properties both in vitro and in vivo, presumably via Dsg2‐mediated regulation of TJ. Mice deficient for intestinal Dsg2 show increased basal permeability and are highly susceptible to experimental colitis. In several cohorts of IBD patients, intestinal protein levels of Dsg2 are reduced and desmosome ultrastructure is altered suggesting that Dsg2 is involved in IBD pathogenesis. In addition to its adhesive function, Dsg2 contributes to enterocyte cohesion and intestinal barrier function. Dsg2 is also involved in enterocyte proliferation, barrier differentiation and induction of apoptosis, in part by regulation of p38MAPK and EGFR signalling. In IBD, the function of Dsg2 appears to be compromised via p38MAPK activation, which is a critical pathway for regulation of desmosomes and is associated with keratin phosphorylation in IBD patients. In this review, the current findings on the role of Dsg2 as a novel promising target to prevent loss of intestinal barrier function in IBD patients are discussed.

中文翻译：

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靶向桥粒粘附和信号传导以稳定炎症性肠病的肠道屏障——来自实验模型和患者的经验教训。

克罗恩病 (CD) 和溃疡性结肠炎 (UC) 等炎症性肠病 (IBD) 具有复杂且多因素的发病机制，但尚未完全了解。与临床症状密切相关的典型特征是肠上皮屏障功能受损。越来越多的证据表明桥粒与紧密连接 (TJ) 和粘附连接 (AJ) 一起形成肠上皮屏障，在 IBD 发病机制中发挥着独特的作用。这是基于以下发现：桥粒蛋白（Dsg）2，一种钙粘蛋白型桥粒粘附分子，是维持体外和体内肠道屏障特性所必需的，大概是通过 Dsg2 介导的 TJ 调节。肠道 Dsg2 缺陷的小鼠表现出增加的基底通透性并且对实验性结肠炎高度敏感。在几个 IBD 患者队列中，Dsg2 的肠道蛋白水平降低，桥粒超微结构改变，表明 Dsg2 参与 IBD 发病机制。除了其粘附功能外，Dsg2 还有助于肠细胞凝聚和肠道屏障功能。Dsg2 还参与肠细胞增殖、屏障分化和诱导细胞凋亡，部分是通过调节 p38MAPK 和 EGFR 信号传导。在 IBD 中，Dsg2 的功能似乎通过 p38MAPK 激活受到损害，这是调节桥粒的关键途径，并且与 IBD 患者的角蛋白磷酸化有关。在这篇综述中，讨论了当前关于 Dsg2 作为预防 IBD 患者肠道屏障功能丧失的新靶点的作用的发现。Dsg2 的肠道蛋白水平降低，桥粒超微结构改变，表明 Dsg2 参与 IBD 发病机制。除了其粘附功能外，Dsg2 还有助于肠细胞凝聚和肠道屏障功能。Dsg2 还参与肠细胞增殖、屏障分化和细胞凋亡的诱导，部分通过调节 p38MAPK 和 EGFR 信号传导。在 IBD 中，Dsg2 的功能似乎通过 p38MAPK 激活受到损害，这是调节桥粒的关键途径，并且与 IBD 患者的角蛋白磷酸化有关。在这篇综述中，讨论了当前关于 Dsg2 作为预防 IBD 患者肠道屏障功能丧失的新靶点的作用的发现。Dsg2 的肠道蛋白水平降低，桥粒超微结构改变，表明 Dsg2 参与 IBD 发病机制。除了其粘附功能外，Dsg2 还有助于肠细胞凝聚和肠道屏障功能。Dsg2 还参与肠细胞增殖、屏障分化和诱导细胞凋亡，部分是通过调节 p38MAPK 和 EGFR 信号传导。在 IBD 中，Dsg2 的功能似乎通过 p38MAPK 激活受到损害，这是调节桥粒的关键途径，并且与 IBD 患者的角蛋白磷酸化有关。在这篇综述中，讨论了当前关于 Dsg2 作为预防 IBD 患者肠道屏障功能丧失的新靶点的作用的发现。