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

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不清楚。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仍然是无法治愈的，往往会导致生活质量显著下降和与医疗保健相关的成本上升。多种因素参与了疾病的发展，这些因素以屏障受损和失调的炎症反应为中心。虽然上皮屏障功能受损的病因和顺序尚不清楚，但肠黏膜中性粒细胞(PMN)的渗透是消除病原体的关键，但如IBD所见，不受控制的PMN流入会导致广泛的组织损伤。因此，已经很好地证明了疾病的活动性以及随后的临床症状与中性粒细胞进入肠道上皮细胞有关。这种快速且精确调控的粘膜PMN募集的多步骤过程受蛋白质-蛋白质相互作用和多糖介导的结合相互作用的控制。特别是，糖基化调节蛋白质-蛋白质与多糖的相互作用，介导在体内平衡和疾病中至关重要的免疫细胞功能。最近的体外和体内证据表明，抗体介导的靶向与顶端糖蛋白CD44v6结合的上皮细胞表达的糖唾液酸路易斯A(SleA)可以抑制中性粒细胞的迁移，改善上皮屏障功能。与IBD相关的是，肠黏膜炎症患者SleA的表达明显增强，提示了该多糖的重要价值。因此，我们想要阐明肠上皮Slea在中性粒细胞重新聚集到炎症的肠粘膜中的作用，因为IBD疾病的活动性和跨上皮中性粒细胞的迁移有很强的联系。深入了解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。

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.