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Targeting epithelium-expressed sialyl Lewis glycans improves colonic mucosal wound healing and protects against colitis
Matthias Kelm, … , Jennifer C. Brazil, Charles A. Parkos
Matthias Kelm, … , Jennifer C. Brazil, Charles A. Parkos
Published May 19, 2020
Citation Information: JCI Insight. 2020;5(12):e135843. https://doi.org/10.1172/jci.insight.135843.
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Research Article Immunology Inflammation

Targeting epithelium-expressed sialyl Lewis glycans improves colonic mucosal wound healing and protects against colitis

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Abstract

Dysregulated healing of injured mucosa is a hallmark of many pathological conditions, including inflammatory bowel disease. Mucosal injury and chronic intestinal inflammation are also associated with alterations in epithelial glycosylation. Previous studies have revealed that inflammation-induced glycan sialyl Lewis A on epithelial CD44v6 acts as a ligand for transmigrating PMNs. Here we report that robust sialylated Lewis glycan expression was induced in colonic mucosa from individuals with ulcerative colitis and Crohn disease as well as in the colonic epithelium of mice with colitis induced by dextran sodium sulfate (DSS). 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 after ligation of epithelial sialyl Lewis glycans. Finally, we showed that GM35-mediated increases in epithelial proliferation and migration were mediated through activation of kinases that signal downstream of CD44v6 (Src, FAK, Akt). These findings suggest that sialylated Lewis glycans on CD44v6 represent epithelial targets for improved recovery of intestinal barrier function and restitution of mucosal homeostasis after inflammation or injury.

Authors

Matthias Kelm, Miguel Quiros, Veronica Azcutia, Kevin Boerner, Richard D. Cummings, Asma Nusrat, Jennifer C. Brazil, Charles A. Parkos

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Figure 5

Ligation of sialyl Lewis glycans by GM35 activates proliferation and migration signaling pathways in human IECs.

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Ligation of sialyl Lewis glycans by GM35 activates proliferation and mig...
(A) Representative immunoblots from IEC monolayers 18 hours after grid wounding and treatment with 10 μg/mL GM35 or an IgG matched control mAb. Data are representative of n = 3 independent experiments. (B) Proposed model showing GM35 engagement of sialyl Lewis glycans on epithelial CD44v6, resulting in increased activation of Src, FAK, and Akt and leading to increased epithelial proliferation and migration and enhanced wound closure.

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