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

Area of Science:

• Immunology
• Glycobiology
• Cell Biology

Background:

• Polymorphonuclear neutrophils (PMNs) are crucial for innate immunity but their dysregulated migration causes tissue damage in inflammatory diseases like IBD.
• The glycoprotein CD11b/CD18 regulates PMN migration and inflammatory functions, with N-linked glycan Lewis X previously shown to block PMN transepithelial migration (TEpM).

Purpose of the Study:

• To investigate the role of glycosylation in CD11b/CD18 function and identify novel glycan targets for modulating PMN activity.
• To explore the potential of targeting specific glycan structures on CD11b/CD18 to inhibit PMN-associated tissue damage.

Main Methods:

• Purification of CD11b/CD18 from human PMNs.
• MALDI TOF Mass Spectrometry (MS) analysis to identify glycan structures.
• Treatment with lectins targeting specific glycans (Galanthus Nivalis and Phaseolus Vulgaris erythroagglutinin) to assess effects on PMN functions.

Main Results:

• Identification of unusual glycan epitopes on CD11b/CD18, including high Mannose and biantennary galactosylated N-glycans.
• Selective targeting of these glycans with lectins altered intracellular signaling, inhibited PMN TEpM, and differentially affected phagocytosis, superoxide release, and apoptosis.
• Biantennary galactose motifs on CD11b/CD18 were highlighted as key targets.

Conclusions:

• Discrete glycan motifs on CD11b/CD18, such as biantennary galactose, represent novel targets for therapeutic intervention.
• Selective manipulation of these glycans can inhibit PMN inflammatory functions and reduce associated tissue damage in chronic inflammatory conditions.