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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 3

GM35 improves healing of biopsy-induced colonic wounds in vivo.

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GM35 improves healing of biopsy-induced colonic wounds in vivo.
(A) Sche...
(A) Schematic overview of experimental design timeline. Animals were wounded on day 0 and treated with GM35 or a control IgG on day 1 via i.p. injection (250 μg/animal) or microinjection directly into the wound bed (10 μg/wound). (B) Percentage of wound healing in animals injected with IgG (blue) or GM35 (red) directly into wound beds. Data are shown as means ± SEM; n = 3 independent experiments. **P < 0.01, ****P < 0.0001. Mann-Whitney U test for day 2 and unpaired t test for day 3. (C) Percentage of wound healing in animals i.p. injected with 250 μg control IgG (blue) or GM35 (red). Data are shown as means ± SEM (n = 3 independent experiments) and were analyzed by 1-way ANOVA followed by Tukey’s post hoc testing. ****P < 0.0001. (D) Representative images of wounds at day 1 and day 3 after i.p. injection with IgG control Ab or GM35. (E) Representative immunofluorescence images of colonic wounds stained with anti-CD44v6 mAb (red) and GM35 (green). Scale bar: 10 μm. Magnification of area adjacent to wound (yellow square) demonstrates expression and colocalization of CD44v6 (red) and sialyl glycan epitopes (GM35, green). (F) Representative immunofluorescence images with proliferation marker Ki67 (pink) in wound-adjacent epithelial crypts after 24 hours of treatment with IgG or GM35. Nuclei are stained in blue. Graph shows quantification of Ki67+ cells in wound-adjacent crypts after treatment with IgG or GM35. Scale bar: 5 μm. Data are shown as mean ± SEM (n = 3 experiments) and were analyzed by 1-way ANOVA followed by Tukey’s post hoc testing. ***P < 0.001.

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