title: Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation.
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 (Le(x)) 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 Le(x) residues within glycan chains had no effect on PMN migration or adhesive interactions. There was increased surface expression of Le(x) on PMN after TEM, and blockade of terminal Le(x) 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 Le(x) represents a potential target for regulating PMN trafficking and function in inflamed mucosa. Furthermore, given its abundant expression on migrating PMN, Le(x) may be a rational target for modulating inflammation in diseases where dysregulated PMN influx is associated with host tissue damage.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: brazilj@med.umich.edu.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Brazil
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pathology, Northwestern University, Chicago, Illinois.
authors.forename: Ronen
authors.initials: R
authors.lastname: Sumagin
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, Georgia.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Department of Neonatal-Perinatal Medicine, Emory University, Atlanta, Georgia.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Louis
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: cparkos@med.umich.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000276:immunology; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D016256:Lewis X Antigen / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*
chemical_list: D016256:Lewis X Antigen