High affinity sugar ligands of C-type lectin receptor langerin

• Published in: Biochimica et biophysica acta Vol. 1862; no. 7; pp. 1592 - 1601
• Main Authors: Ota, Fumi, Hirayama, Tetsuya, Kizuka, Yasuhiko, Yamaguchi, Yoshiki, Fujinawa, Reiko, Nagata, Masahiro, Ismanto, Hendra S., Lepenies, Bernd, Aretz, Jonas, Rademacher, Christoph, Seeberger, Peter H., Angata, Takashi, Kitazume, Shinobu, Yoshida, Keiichi, Betsuyaku, Tomoko, Kida, Kozui, Yamasaki, Sho, Taniguchi, Naoyuki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2018
• Subjects: Antigens, CD - chemistry; Antigens, CD - metabolism; Antigens, Surface - chemistry; Antigens, Surface - metabolism; Bronchoalveolar Lavage Fluid - chemistry; C-type lectin; Chronic obstructive pulmonary disease (COPD); Cytokines - metabolism; Dendritic Cells - metabolism; Disaccharides - chemistry; Disaccharides - metabolism; Disaccharides - therapeutic use; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Galactose - metabolism; Glycobiology; Humans; Keratan sulfate; Keratan Sulfate - chemistry; Keratan Sulfate - metabolism; Langerin; Lectins, C-Type - chemistry; Lectins, C-Type - metabolism; Ligands; Mannose-Binding Lectins - chemistry; Mannose-Binding Lectins - metabolism; Protein Binding; Protein Isoforms - metabolism; Pulmonary Emphysema - drug therapy; Pulmonary Emphysema - metabolism; Recombinant Proteins - metabolism; langerin-L; Chronic obstructive pulmonary disease (COPD); Langerin; Keratan sulfate; BALF; CLR; KS; L4; Tri; Gal; Glycobiology; CRD; ITAM; LC; langerin-S; ITC; DC; COPD; C-type lectin
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2018.04.004

Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs. •Anti-inflammatory disaccharide L4 selectively binds to C-type lectin receptor langerin.•Synthesized oligomeric L4 derivatives display over 1000-fold higher affinity to langerin.•L4 and its derivatives are useful for understanding langerin function and for therapeutic application.