The role of sialyl Lewis A during neutrophil transepithelial migration in chronic inflammatory bowel diseases

唾液酸Lewis A在慢性炎症性肠病中性粒细胞跨上皮迁移过程中的作用

• 批准号: 410855404
• 负责人: Dr. Matthias Kelm
• 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: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410855404?language=en
• 关键词: role; sialyl; Lewis; during; neutrophil

Inflammatory Bowel Diseases (IBD) including ulcerative colitis represent an enormous therapeutic challenge since its pathophysiology is still not understood in detail yet. Despite major efforts in basic and clinical research and the implementation of new drugs, IBD remains incurable often resulting in a remarkable reduction of life quality and escalating health care related costs. Multiple factors contribute to the development of the disease that center around impaired barrier and a dysregulated inflammatory response. While etiology and sequence of impaired epithelial barrier function remains unclear, intestinal mucosal infiltration of polymorphonuclear neutrophils (PMN) is essential for pathogen elimination but uncontrolled mucosal PMN influx leads to extensive tissue damage as seen in IBD. Thus, it has been well documented that disease activity and, subsequently, clinical symptoms are linked to the influx of PMNs into intestinal epithelium. This rapid and precisely-regulated multistep process of mucosal PMN recruitment is controlled by protein-protein interactions and glycan mediated binding interactions. In particular, glycosylation modulates protein-protein interactions with glycans mediating crucial immune cell functions in both homeostasis and disease. Recent in vitro and in vivo evidence has indicated that antibody-mediated targeting of epithelial expressed glycan sialyl Lewis A (sLea) binding to apical glycoprotein CD44v6 inhibits neutrophil migration and improves epithelial barrier function. Related to IBD, patients with inflamed intestinal mucosa show a marked expression of sLea indicating the important value of this glycan. Therefore, we want to elucidate the role of intestinal epithelial sLea during neutrophil recruitment into the inflamed intestinal mucosa due the strong link between IBD disease activity and transepithelial neutrophil migration. A deeper knowledge of the role of sLea in this process will provide new insights into the pathophysiology of IBD to identify new therapeutic approaches.

包括溃疡性结肠炎在内的炎症性肠病（IBD）是一个巨大的治疗挑战，因为其病理生理机制尚未被详细了解。尽管在基础和临床研究以及新药的实施方面做出了重大努力，但IBD仍然无法治愈，经常导致生活质量显著降低和医疗保健相关费用不断上升。多种因素导致疾病的发展，这些因素以屏障受损和炎症反应失调为中心。虽然上皮屏障功能受损的病因和顺序尚不清楚，但肠粘膜多形核中性粒细胞（PMN）浸润对于病原体清除至关重要，但不受控制的粘膜PMN流入导致广泛的组织损伤，如IBD所见。因此，它已被充分证明，疾病的活动，并随后，临床症状与流入的中性粒细胞进入肠上皮细胞。这种快速和精确调节的多步骤粘膜PMN募集过程由蛋白质-蛋白质相互作用和聚糖介导的结合相互作用控制。特别是，糖基化调节蛋白质-蛋白质相互作用，聚糖介导稳态和疾病中的关键免疫细胞功能。最近的体外和体内证据表明，抗体介导的靶向上皮表达的聚糖唾液酸刘易斯A（sLea）与顶端糖蛋白CD 44 v6的结合抑制了中性粒细胞迁移并改善了上皮屏障功能。与IBD相关，患有发炎的肠粘膜的患者显示sLea的显著表达，表明该聚糖的重要价值。因此，我们希望阐明肠上皮sLea在中性粒细胞募集到发炎的肠粘膜中的作用，这是由于IBD疾病活动与中性粒细胞跨上皮迁移之间的密切联系。 更深入地了解sLea在这一过程中的作用将为IBD的病理生理学提供新的见解，以确定新的治疗方法。