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

• Applicant: Dr. Matthias Kelm
• Subject Area: General and Visceral Surgery
• Term: from 2018 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410855404

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Charles Parkos, Ph.D.