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Novel Role of Lewis A Glycans in Regulating Neutrophil Trafficking
Author(s) -
Brazil Jennifer C,
Sumagin Ronen,
Lee Goo,
Louis Nancy A,
Cummings Richard D,
Parkos Charles A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.469.2
Subject(s) - glycan , fucosylation , fucosyltransferase , glycobiology , sialyl lewis x , innate immune system , biology , chemotaxis , microbiology and biotechnology , immunology , inflammation , chemistry , selectin , immune system , biochemistry , glycoprotein , receptor , gene
Pathogen‐triggered neutrophil (PMN) recruitment is critical for innate immunity, but aberrant PMN influx is also implicated in the pathogenesis of numerous inflammatory diseases of the gut and lungs. Fucosylated terminal glycans from the Lewis glycan family, such as Lewis‐x (Le x ) and Sialyl Lewis‐x, have previously been implicated in the regulation of important PMN functions, including Selectin‐mediated PMN transendothelial trafficking. While such glycans based on the type 2 sequence (Galb1‐4GlcNAc‐R) are abundant on PMNs, the presence of type 1 Galb1‐3GlcNAc‐R glycans required for the expression of Lewis‐a (Le a ) have not yet been reported. Here, we conclusively report that Le a is expressed in human PMNs as probed using mAbs whose specificity was confirmed using glycan array technology. Le a function was further probed using Le a ‐selective mAbs and a Le a binding lectin resulting in increased PMN chemotaxis and migration across model intestinal epithelia. Analyses of glycan synthetic machinery in PMN revealed expression of a b1–3 Galactosyltransferase and an α1–4 Fucosyltransferase, glycosyltransferases that are required for Le a synthesis. Specificity of findings to Le a was confirmed by absence of antibody‐mediated effects using PMN from individuals deficient in α1–4 fucosylation. These results suggest that PMN expression of Le a has important functional consequences that may be relevant during PMN trafficking within inflamed mucosal tissues. We therefore propose that PMN Le a represents a new target for regulating intestinal innate immunity and modulating inflammation in diseases where dysregulated PMN influx is associated with bystander tissue damage. Furthermore, differential responses of human PMN to physiological ligands of Le a (based on an individuals Lewis phenotype) may provide insights into the mechanisms linking specific Lewis phenotypes with differential susceptibilities to bacterial infections, viral infections and coronary heart disease. Support or Funding Information NIH ‐ RO1 DK072564‐21 (Parkos) CCFA ‐ Career Development Award (314660) (Brazil)