LAUSR

Dysregulated healing of injured mucosa is a hallmark of many pathological conditions including inflammatory bowel disease. Mucosal injury and chronic inflammation including persistent neutrophil (PMN) infiltration are also associated with alterations in epithelial glycosylation. Previous studies have revealed the inflammation induced glycan sLea on epithelial CD44v6 acts as a ligand for transmigrating PMN. Furthermore, blocking sLea-mediated binding interactions with the mAb GM35 reduced PMN transepithelial migration. Here we report that robust sialylated Lewis glycan expression is induced in colonic mucosa from individuals with ulcerative colitis (UC) and Crohn's disease (CD) as well as in colonic epithelium of mice with DSS colitis. Targeting of sialylated epithelial Lewis glycans with mAb GM35 reduced disease activity and improved mucosal integrity during DSS induced colitis in mice. Wound healing studies revealed increased epithelial proliferation and migration responses as well as improved mucosal repair following ligation of epithelial sialyl Lewis glycans. Finally, we show GM35-mediated increases in epithelial proliferation and migration are mediated through activation of kinases that signal downstream of CD44v6 (Src, FAK, Akt). These findings suggest that sialylated Lewis glycans on epithelial CD44v6 may represent targets for improved recovery of epithelial barrier function and restitution of mucosal homeostasis following intestinal inflammation or injury.