RT Journal Article SR Electronic T1 The fungal ligand chitin directly binds and signals inflammation dependent on oligomer size and TLR2 JF bioRxiv FD Cold Spring Harbor Laboratory SP 270405 DO 10.1101/270405 A1 Katharina Fuchs A1 Yamel Cardona Gloria A1 Olaf-Oliver Wolz A1 Franziska Herster A1 Lokesh Sharma A1 Carly Dillen A1 Christoph Täumer A1 Sabine Dickhöfer A1 Zsofia Bittner A1 Truong-Minh Dang A1 Anurag Singh A1 Daniel Haischer A1 Maria A. Schlöffel A1 Kirsten J. Koymans A1 Tharmila Sanmuganantham A1 Milena Krach A1 Nadine A. Schilling A1 Felix Frauhammer A1 Lloyd Miller A1 Thorsten Nürnberger A1 Salomé LeibundGut-Landmann A1 Andrea A. Gust A1 Boris Macek A1 Martin Frank A1 Cécile Gouttefangeas A1 Charles S. Dela Cruz A1 Dominik Hartl A1 Alexander N.R. Weber YR 2018 UL http://biorxiv.org/content/early/2018/03/05/270405.abstract AB Chitin is a highly abundant polysaccharide and linked to fungal infection and asthma. Unfortunately, its polymeric structure has hampered the identification of immune receptors directly binding chitin and signaling immune activation and inflammation, because purity, molecular structure and molarity are not well definable for a polymer typically extracted from biomass. Therefore, by using defined chitin (N-acetyl-glucosamine) oligomers, we identified six subunit long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR) 2 as the primary fungal chitin receptor on human and murine immune cells. Chitin oligomers directly bound TLR2 with nanomolar affinity and showed both overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Conversely, chitin oligomers shorter than 6 subunits were inactive or showed antagonistic effects on chitin/TLR2-mediated signaling, hinting to a size-dependent sensing/activation system unexpectedly conserved in plants and humans. Since blocking the chitin-TLR2 interaction effectively prevented 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.