Targeting of Lewis‐X‐containing glycans blocks PMN transepithelial migration and increases phagocytosis and degranulation (488.3)

Abstract

The transepithelial migration (TEM) of neutrophils (PMN) is a histopathological hallmark of inflammatory bowel disease (IBD), yet the mechanisms controlling PMN TEM remain poorly defined. The fucosylated, terminal glycan determinant Lewis X (Lex), expressed on the glycans of PMN surface glycoproteins (including MAC‐1 and LFA‐1), has previously been implicated in adhesive interactions between PMN and endothelium. However, little is known about the role of Lex in PMN function following extravasation. Flow cytometry analyses revealed increased surface expression of Lex on human PMN following TEM, while immunohistochemistry demonstrated robust expression of PMN‐associated Lex within crypt abscesses in the colonic epithelium of individuals with IBD. Furthermore, engagement of Lex increased PMN adhesive interactions, both with other PMNs and with intestinal epithelial cells, blocking PMN chemotaxis and TEM. In addition to blocking PMN trafficking, targeting of Lex also altered post‐migratory PMN functions, increasing both PMN phagocytosis of Salmonella enterica and release of primary granules. Therefore, glycans expressing the Lex determinant represent a novel target for regulating both the trafficking of PMN into the intestinal lumen and PMN function. Further, given its robust expression in migrating PMN and during inflammation, Lex may be a rational target for modulating inflammation in IBD.Grant Funding Source: Supported by Crohn's & Colitis Foundation of America and National Institutes of Health