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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 1

Increased expression of CD44v6 and sialyl Lewis glycans in inflamed murine and human intestinal mucosa.

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Increased expression of CD44v6 and sialyl Lewis glycans in inflamed muri...
Immunohistochemical analysis of healthy colonic mucosa and colonic mucosa from patients with IBD. Representative images from normal uninflamed mucosa (A) are compared with active ulcerative colitis (UC) (B). Noninflamed mucosa (C) and adjacent inflamed tissue (D) from Crohn disease (CD) are also compared. (E) Quantification of intensity of staining from n = 3 normal colonic mucosa or colonic mucosa from n = 3 patients with UC or CD. Data are shown as means ± SEM and were analyzed by 1-way ANOVA followed by Tukey’s post hoc testing. **P < 0.01. Expression of CD44v6 (red), Muc-2 (red), or sialyl Lewis glycans stained with GM35 (green) in representative images of normal colonic mucosa (F) and inflamed colonic mucosa (G) of WT C57BL/6J mice given 2.5% DSS for 5 days. Images are representative of n = 3 independent experiments. Scale bar: 10 μm.

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