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

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 FrauhammerLloyd S Miller, Thorsten Nürnberger, Salomé LeibundGut-Landmann, Andrea A. Gust, Boris Macek, Martin Frank, Cécile Gouttefangeas, Charles S. Dela Cruz, Dominik Hartl, Alexander N.R. Weber

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere201846065
JournalEMBO Reports
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • anti-fungal innate immunity
  • chitin
  • inflammation
  • N-acetyl-glucosamine
  • toll-like receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Fuchs, K., Cardona Gloria, Y., Wolz, O. O., Herster, F., Sharma, L., Dillen, C. A., Täumer, C., Dickhöfer, S., Bittner, Z., Dang, T. M., Singh, A., Haischer, D., Schlöffel, M. A., Koymans, K. J., Sanmuganantham, T., Krach, M., Roger, T., Le Roy, D., Schilling, N. A., ... Weber, A. N. R. (Accepted/In press). The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size. EMBO Reports, [e201846065]. https://doi.org/10.15252/embr.201846065