Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing.

• Type of Material: Article
• Authors: Ronen Sumagin, Northwestern University; JC Brazil, University of Michigan Medical School; P Nava, Instituto Politécnico Nacional; H Nishio, Emory University; Mohammad Alam, Emory University; AC Luissint, University of Michigan Medical School; Dominique Weber, Emory University; Andrew Neish, Emory University; Asma Nusrat, Emory University; Charles Parkos, Emory University
• Language: English
• Date: 2016-01-06
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: & 2016 Society for Mucosal Immunology
• Final Published Version (URL): http://dx.doi.org/10.1038/mi.2015.135
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Volume: 9
• Issue: 5
• Start Page: 1151
• End Page: 1162
• Grant/Funding Information: This work was supported in part by grants from the NIH (DK072564, DK061379, DK079392 to CP, and DK055679, DK059888 to A.N.), CDA from the Crohn’s and Colitis Foundation of America to J.C.B., and NIH K01 DK101675 to R.S.; We thank Emory University’s Digestive Disease Research and Development Center core facility for culturing intestinal epithelial cell lines (supported by National Institutes of Health [NIH] DK064399).; This work was supported in part by grants from the NIH (DK072564, DK061379, DK079392 to CP, and DK055679, DK059888 to AN), CDA from the Crohn’s and Colitis Foundation of America to JCB, and NIH K01 DK101675 to RS.
• Research Categories: Health Sciences, Pathology

Abstract

A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. Although epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and β-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal-injury model, we demonstrated epithelial ICAM-1 has an important role in activation of epithelial Akt and β-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing.Mucosal Immunology advance online publication, 6 January 2016; doi:10.1038/mi.2015.135.