Implication of C-type lectin receptor langerin and keratan sulfate disaccharide in emphysema

Glycosylation is profoundly involved in various diseases, and interactions between glycan binding proteins and their sugar ligands are plausible drug targets. Keratan sulfate (KS), a glycosaminoglycan, is downregulated in lungs by cigarette smoking, suggesting that KS is involved in smoking-related diseases, such as chronic obstructive pulmonary disease (COPD). We found that a highly sulfated KS disaccharide, L4, suppresses lung inflammation and is effective against COPD and its exacerbation in mouse models. Its anti-inflammatory activity was comparable to that of a steroid. As a possible mechanism, langerin, a C-type lectin receptor (CLR) expressed in dendritic cells, was suggested to function as an L4 receptor. Oligomeric L4 derivatives were chemically designed to create new ligands with higher affinity and activity. The synthetic L4 oligomers bound to langerin with over 1000-fold higher affinity than the L4 monomer, suggesting that these compounds are effective drug candidates against COPD and inflammatory diseases.