Targeting of Lewis‐a glycans accelerates chemotaxis and transepithelial migration by human PMNs (650.9)

Abstract

Pathogen‐triggered neutrophil (PMN) recruitment is critical for innate immunity, but aberrant PMN influx into intestinal crypts marks disease severity in inflammatory bowel disease (IBD). Fucosylated terminal glycans, such as Lewis‐x (Lex) and Sialyl Lewis‐x, have previously been implicated in the regulation of important PMN functions, including selectin‐mediated PMN trafficking. While such glycans based on the type 2 sequence (Galβ1‐4GlcNAc‐R) are abundant on PMNs, it was previously thought that PMNs lack type 1 glycans (Galβ1‐3GlcNAc‐R) required for the expression of Lewis‐a (Lea). Here, we demonstrate through immunoblot, flow cytometry, and immunohistochemical analyses of tissues from individuals with IBD, that Lea is in fact present on human PMNs. Further, immunoblotting revealed robust PMN expression of Fucosyltransferase 3/5, glycosyltransferases with α1/4 fucosyltransferase activity, required for the terminal step in Lea synthesis. We further report that treatment of PMN with Lea‐specific Abs increases both chemotaxis across collagen and migration across model intestinal epithelia. Thus, we identify novel expression of Lea by human PMN and demonstrate its relevance to PMN trafficking within the intestine. PMN Lea represents a novel target for regulating intestinal innate immunity and 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