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

Abstract

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.

• Authors: Katharina Fuchs, Yamel Cardona Gloria, Olaf-Oliver Wolz, Franziska Herster, Lokesh Sharma, Carly A Dillen, Christoph Täumer, Sabine Dickhöfer, Zsofia Bittner, Truong-Minh Dang, Anurag Singh, Daniel Haischer, Maria A Schlöffel, Kirsten J Koymans, Tharmila Sanmuganantham, Milena Krach, Thierry Roger, Didier Le Roy, Nadine A Schilling, Felix Frauhammer, Lloyd S Miller, Thorsten Nürnberger, Salomé LeibundGut-Landmann, Andrea A Gust, Boris Macek, Martin Frank, Cécile Gouttefangeas, Charles S Dela Cruz, Dominik Hartl, Alexander Nr Weber
• Journal: EMBO reports (EMBO Rep) Vol. 19 Issue 12 (12 2018) ISSN: 1469-3178 [Electronic] England
• PMID: 30337494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors.

Chemical References

• Immunologic Factors
• Ligands
• Toll-Like Receptor 1
• Toll-Like Receptor 2
• Chitin
• Zymosan
• Chitinases

Topics

• Animals
• Cell Wall (drug effects, metabolism)
• Chitin (chemistry, metabolism)
• Chitinases (metabolism)
• Female
• Fungi (metabolism)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Immunologic Factors (pharmacology)
• Inflammation (metabolism, pathology)
• Ligands
• Lymphocytes (drug effects, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• THP-1 Cells
• Toll-Like Receptor 1 (agonists, metabolism)
• Toll-Like Receptor 2 (chemistry, metabolism)
• Zymosan (metabolism)