Functional characterization of JAM-A in neutrophil transepithelial migration during intestinal mucosal inflammation

JAM-A在肠粘膜炎症过程中中性粒细胞跨上皮迁移中的功能特征

• 批准号: 329865901
• 负责人: Privatdozent Dr. Sven Flemming
• 金额: --
• 依托单位: Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329865901?language=en
• 关键词: Functional; characterization; JAM; neutrophil; transepithelial

Inflammatory Bowel Disease (IBD) encompassing Crohns disease and ulcerative colitis are chronic relapsing disorders. The etiology of IBD is multifactorial and remains incompletely understood; however trigger factors are driven by genetic predisposition, environmental factors and mucosal epithelial barrier dysfunction that lead to dysregulated immune responses against microflora-derived antigens and massive recruitment of neutrophils (PMN) (first responders of innate immunity against bacteria) into the intestinal mucosa. The migration of PMN across the single layer of epithelial cells (IECs) that covers the intestinal mucosa is a multiple step process that includes PMN adhesion to the basal membrane of IECs, migration between IECs and interactions at the apical epithelial surface at the intestinal lumen. PMN migration between IECs (paracellular migration) involves crossing epithelial intercellular junction protein complexes, desmosomes, adherens junction and tight junction (TJ) that are sequentially localized from the basal membrane to apical side. However, in contrast to PMN migration across the endothelial barrier (transendothelial migration) the molecular mechanisms involved in PMN in transepithelial migration (TEpM) remain to be elucidated. A TJ associated transmembrane protein termed Junctional Adhesion Molecule-A (JAM-A) has been shown to play an important role in the maintenance of epithelial barrier function and regulate PMN migration across vascular endothelium [1]. JAM-A is also expressed on leukocytes including PMN, however, the specific contributions of epithelial versus leukocyte JAM-A in controlling TEpM are unclear and require further investigation. The overall goal of this proposal is to decipher the role of JAM-A in PMN TEpM during intestinal mucosal inflammation such as IBD using in-vivo approaches. This study will help to better characterize the molecular interactions between IECs and PMN that are involved in the PMN TEpM process. Furthermore, it will provide new insights for therapeutic strategies that aim to decrease immune responses in inflammatory disorders.

炎症性肠病(IBD)包括克罗恩病和溃疡性结肠炎，均为慢性复发性疾病。IBD的病因是多因素的，至今仍不完全清楚；然而，触发因素是由遗传易感性、环境因素和粘膜上皮屏障功能障碍驱动的，这些功能障碍导致对微生物衍生抗原的免疫反应失调，以及中性粒细胞(PMN)(天然免疫的第一反应者)大量募集到肠粘膜。PMN在覆盖肠粘膜的单层上皮细胞(IECS)上的迁移是一个多步骤的过程，包括PMN与IECS基底膜的黏附、IECS之间的迁移和肠腔顶端上皮面的相互作用。PMN在IECs之间的迁移(Paraccell Migration)涉及上皮细胞间连接蛋白复合体、桥粒、粘着连接和紧密连接(TJ)，这些连接从基底膜到顶端依次定位。然而，与PMN跨内皮屏障迁移(跨内皮迁移)相反，PMN在跨上皮迁移(TEpM)中涉及的分子机制仍未阐明。一种与TJ相关的跨膜蛋白JAM-A(JAM-A)被证明在维持上皮屏障功能和调节PMN跨血管内皮细胞迁移方面发挥重要作用[1]。JAM-A也表达在包括PMN在内的白细胞上，然而，上皮细胞和白细胞JAM-A在控制TEpM中的具体作用尚不清楚，需要进一步研究。这项提案的总体目标是使用体内方法破译JAM-A在肠粘膜炎症(如IBD)中的PMN TEpM中的作用。这项研究将有助于更好地表征参与PMN TEpM过程的IECS和PMN之间的分子相互作用。此外，它将为旨在降低炎症性疾病免疫反应的治疗策略提供新的见解。