The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size

• Published in: EMBO reports Vol. 19; no. 12
• Main Authors: Fuchs, Katharina, Cardona Gloria, Yamel, Wolz, Olaf‐Oliver, Herster, Franziska, Sharma, Lokesh, Dillen, Carly A, Täumer, Christoph, Dickhöfer, Sabine, Bittner, Zsofia, Dang, Truong‐Minh, Singh, Anurag, Haischer, Daniel, Schlöffel, Maria A, Koymans, Kirsten J, Sanmuganantham, Tharmila, Krach, Milena, Roger, Thierry, Le Roy, Didier, Schilling, Nadine A, Frauhammer, Felix, Miller, Lloyd S, Nürnberger, Thorsten, LeibundGut‐Landmann, Salomé, Gust, Andrea A, Macek, Boris, Frank, Martin, Gouttefangeas, Cécile, Dela Cruz, Charles S, Hartl, Dominik, Weber, Alexander NR
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2018; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Animals; anti‐fungal innate immunity; Asthma; Cell Wall - drug effects; Cell Wall - metabolism; Chitin; Chitin - chemistry; Chitin - metabolism; Chitinases - metabolism; EMBO19; EMBO23; EMBO37; Female; Fungal diseases; Fungal infections; Fungi; Fungi - metabolism; Glucosamine; Humans; Hydrophobic and Hydrophilic Interactions; Immune response; Immune system; Immunologic Factors - pharmacology; In vivo methods and tests; Inflammation; Inflammation - metabolism; Inflammation - pathology; Ligands; Lymphocytes - drug effects; Lymphocytes - metabolism; Mice, Inbred C57BL; Mice, Knockout; N‐acetyl‐glucosamine; Oligomers; Polysaccharides; Receptors; Scientific Report; Scientific Reports; Signaling; THP-1 Cells; TLR2 protein; Toll-Like Receptor 1 - agonists; Toll-Like Receptor 1 - metabolism; Toll-Like Receptor 2 - chemistry; Toll-Like Receptor 2 - metabolism; Toll-like receptors; toll‐like receptor; Zymosan - metabolism; anti‐fungal innate immunity; inflammation; toll‐like receptor; N‐acetyl‐glucosamine; chitin
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201846065

Chitin is the second most abundant polysaccharide in nature and linked to fungal infection and asthma. However, bona fide immune receptors directly binding chitin and signaling immune activation and inflammation have not been clearly identified because polymeric crude chitin with unknown purity and molecular composition has been used. By using defined chitin (N‐acetyl‐glucosamine) oligomers, we here identify six‐subunit‐long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll‐like receptor (TLR2) as a primary fungal chitin sensor on human and murine immune cells. Chitin oligomers directly bind TLR2 with nanomolar affinity, and this fungal TLR2 ligand shows overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Unexpectedly, chitin oligomers composed of five or less subunits are inactive, hinting to a size‐dependent system of immuno‐modulation that appears conserved in plants and humans. Since blocking of the chitin‐TLR2 interaction effectively prevents chitin‐mediated inflammation in vitro and in vivo , our study highlights the chitin‐TLR2 interaction as a potential target for developing novel therapies in chitin‐related pathologies and fungal disease. Synopsis Chitin, a polysaccharide linked to fungal infection and allergic asthma, directly binds to the innate immune receptor TLR2 and triggers inflammation dependent on oligomer size. Blocking the chitin‐TLR2 interaction effectively prevents chitin‐mediated inflammation. Oligomeric chains of fungal chitin directly bind to TLR2 and trigger inflammation. Blocking of the chitin‐TLR2 interaction prevents chitin‐mediated inflammation in vitro and in vivo . Size‐dependent chitin recognition based on oligomers is found in both plants and humans. Graphical Abstract Chitin, a polysaccharide linked to fungal infection and allergic asthma, directly binds to the innate immune receptor TLR2 and triggers inflammation dependent on oligomer size. Blocking the chitin‐TLR2 interaction effectively prevents chitin‐mediated inflammation.