Targeting of neutrophil lewis X blocks transepithelial migration and increases phagocytosis and degranulation

Jennifer C. Brazil*, Ronen Sumagin, Richard D. Cummings, Nancy A. Louis, Charles A. Parkos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Polymorphonuclear leukocytes (PMNs) are innate immune cells whose principal function is to migrate from the blood to sites of inflammation, where they exert crucial anti-infectious and immunomodulatory effects. However, dysregulated migration of PMNs into mucosal epithelial tissues is characteristic of chronic inflammatory disorders, including inflammatory bowel disease. Carbohydrate-mediated binding interactions between PMN Lewis glycans and endothelial glycan-binding proteins are critical for initial migration of PMN out of the vasculature. However, the role of Lewis glycans during transepithelial migration (TEM) has not been well characterized. Herein, we show that antibody blockade of Lewis X (Lex) displayed as terminal glycan residues on the PMN surface blocks chemotaxis and TEM while enhancing PMN-adhesive interactions with intestinal epithelia. Unexpectedly, targeting of subterminal Lex residues within glycan chains had no effect on PMN migration or adhesive interactions. There was increased surface expression of Lex on PMN after TEM, and blockade of terminal Lex regulated post-migratory PMN functions, increasing PMN phagocytosis and the surface mobilization of azurophilic (CD63, myeloperoxidase, and neutrophil elastase) and specific (CD66b and lactoferrin) granule markers. These findings suggest that terminal Lex represents a potential target for regulating PMN trafficking and function in inflamed mucosa. Furthermore, given its abundant expression on migrating PMN, Lex may be a rational target for modulating inflammation in diseases where dysregulated PMN influx is associated with host tissue damage.

Original languageEnglish (US)
Pages (from-to)297-311
Number of pages15
JournalAmerican Journal of Pathology
Volume186
Issue number2
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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