Targeting Epithelial Expressed Sialylated Lewis glycans improves colonic mucosal wound healing and protects against colitis

Abstract

Delayed healing of mucosal wounds is a hallmark of many pathological conditions including inflammatory bowel disease (IBD). Mucosal wound healing involves a complex interplay between epithelial cells and infiltrating immune cells that trigger cell signaling events and epithelial cell migration, proliferation and differentiation that are necessary for restoration of mucosal homeostasis. Specific alterations in surface glycosylation have been reported in intestinal epithelial cells following injury and we have shown that targeting the inflammation induced glycan sialyl Lewis A (sLea) on epithelial CD44v6 (with a specific mAb termed GM35) results in inhibition of neutrophil (PMN) trafficking in the inflamed intestine. Despite this observation, the role of glycans in intestinal wound healing has not been examined. Here we report that selective targeting of sialylated Lewis glycans on epithelial glycoprotein CD44v6 increases human intestinal epithelial cell proliferation, migration and wound healing. Furthermore, direct injection of GM35 into biopsy‐induced colonic wounds as well as systemic injection resulted in a significant increase in epithelial proliferation and mucosal wound closure in vivo. These glycan mediated increases in epithelial proliferation were found to be mediated through the activation of Src, Fak and Akt (kinases previously shown to signal downstream of CD44v6 engagement). Finally, systemic administration of GM35 to C57BL/6J mice followed by induction of colitis with dextran sodium sulfate resulted in reduced disease activity, as assessed clinically and histologically, when compared to mice treated with an isotype control mAb. Given our observations of robust upregulation of sialylated Lewis glycans during intestinal inflammation in mice and humans, these data suggest that targeting sLea on epithelial CD44v6 may represent a promising new target for improved recovery of epithelial barrier function and restitution of intestinal homeostasis following inflammation or injury.Support or Funding InformationThis work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation – 410855404), a senior Research Award from the Crohn’s and Colitis Foundation (CCF) and R01 awards from the NIH (DK072564 and DK079392).