[HTML][HTML] Regulation of neutrophil function by selective targeting of glycan epitopes expressed on the integrin CD11b/CD18

M Kelm, S Lehoux, V Azcutia… - … : official publication of …, 2020 - ncbi.nlm.nih.gov
M Kelm, S Lehoux, V Azcutia, RD Cummings, A Nusrat, CA Parkos, JC Brazil
FASEB journal: official publication of the Federation of American …, 2020ncbi.nlm.nih.gov
Polymorphonuclear neutrophils (PMN) play a critical role in the innate immune response to
invading pathogens. However, dysregulated mucosal trafficking of PMN and associated
epithelial tissue damage is a pathological hallmark of numerous inflammatory conditions
including inflammatory bowel disease. The glycoprotein CD11b/CD18 plays a well
described role in regulating PMN transepithelial migration and PMN inflammatory functions.
Previous studies have demonstrated that targeting of the N-linked glycan Lewis X on CD11b …
Abstract
Polymorphonuclear neutrophils (PMN) play a critical role in the innate immune response to invading pathogens. However, dysregulated mucosal trafficking of PMN and associated epithelial tissue damage is a pathological hallmark of numerous inflammatory conditions including inflammatory bowel disease. The glycoprotein CD11b/CD18 plays a well described role in regulating PMN transepithelial migration and PMN inflammatory functions. Previous studies have demonstrated that targeting of the N-linked glycan Lewis X on CD11b blocks PMN transepithelial migration (TEpM). Given evidence of glycosylation dependent regulation of CD11b/CD18 function, we performed MALDI TOF Mass Spectrometry (MS) analyses on CD11b/CD18 purified from human PMN. Unusual glycan epitopes identified on CD11b/CD18 included high Mannose oligosaccharides recognized by the Galanthus Nivalis (GNA) lectin and biantennary galactosylated N-glycans recognized by the Phaseolus Vulgaris erythroagglutinin (PHA-E) lectin. Importantly, we show that selective targeting of glycans on CD11b with such lectins results in altered intracellular signaling events that inhibit TEpM and differentially affect key PMN inflammatory functions including phagocytosis, superoxide release and apoptosis. Taken together, these data demonstrate that discrete glycan motifs expressed on CD11b/CD18 such as biantennary galactose could represent novel targets for selective manipulation of CD11b function and reduction of PMN associated tissue damage in chronic inflammatory diseases.
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