Expression of Lewis-a glycans on polymorphonuclear leukocytes augments function by increasing transmigration

Area of Science:

• Immunology
• Glycobiology
• Cell Biology

Background:

• Fucosylated glycans like Lewis-x (Le^x) and sialyl Lewis-x (sLe^x) on neutrophils (PMNs) regulate PMN functions, including trafficking.
• The presence of Lewis-A (Le^a), a stereoisomer of Le^x, on PMNs has not been previously reported.

Purpose of the Study:

• To investigate the expression and function of Lewis-A (Le^a) on human neutrophils (PMNs).
• To determine if Le^a expression on PMNs regulates their migration and to explore its role in innate immunity.

Main Methods:

• Utilized monoclonal antibodies (mAbs) and glycan array technology to identify and characterize Le^a epitopes on PMNs.
• Assessed PMN transmigration across model intestinal epithelia using Le^a-selective probes.
• Analyzed glycan synthetic machinery in PMNs, including relevant glycosyltransferases and fucosyltransferases.
• Confirmed functional effects by testing PMNs from individuals with deficiencies in α1-4 fucosylation.

Main Results:

• Lewis-A (Le^a) is abundantly expressed on human neutrophils (PMNs).
• Engagement of Le^a on PMNs significantly enhances their transmigration across intestinal epithelial models, independent of epithelial Le^a.
• PMNs express the necessary enzymes (β1-3 galactosyltransferase and α1-4 fucosyltransferase) for Le^a synthesis.
• Functional effects of Le^a ligation on migration were confirmed by the lack of enhancement in PMNs deficient in α1-4 fucosylation.

Conclusions:

• Lewis-A (Le^a) is expressed on human PMNs and actively enhances their migration.
• PMN-expressed Le^a represents a novel target for therapeutic strategies aimed at modulating inflammatory responses and intestinal innate immunity.