Targeting Epithelial Expressed Sialyl Lewis A Improves Intestinal Mucosal Wound Healing and Protects Against Colitis

Abstract

Dysregulated 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 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 epithelial glycan sialyl Lewis A (sLea) 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, in addition to inhibiting PMN transepithelial migration, targeting epithelial expressed sLea increases intestinal epithelial wound healing and recovery from barrier disruption in vitro. We report that these protective effects are mediated through deactivation of Akt (a kinase previously shown to destabilize epithelial adherens junctions) downstream of sLea engagement. Furthermore, wound bed injection of GM35 directly into biopsy‐induced colonic wounds resulted in a significant increase in mucosal wound healing in vivo. Finally, 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, compared to mice treated with an isotype control mAb. Given our observations of robust upregulation of epithelial sLea during intestinal inflammation in mice and humans, these data suggest that targeting sLea may represent a promising new target for regulating intestinal trafficking of PMNs. In addition, targeting of this glycan may also provide an additional therapeutic strategy 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).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.