TY - JOUR
T1 - The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size
AU - Fuchs, Katharina
AU - Cardona Gloria, Yamel
AU - Wolz, Olaf Oliver
AU - Herster, Franziska
AU - Sharma, Lokesh
AU - Dillen, Carly A.
AU - Täumer, Christoph
AU - Dickhöfer, Sabine
AU - Bittner, Zsofia
AU - Dang, Truong Minh
AU - Singh, Anurag
AU - Haischer, Daniel
AU - Schlöffel, Maria A.
AU - Koymans, Kirsten J.
AU - Sanmuganantham, Tharmila
AU - Krach, Milena
AU - Roger, Thierry
AU - Le Roy, Didier
AU - Schilling, Nadine A.
AU - Frauhammer, Felix
AU - Miller, Lloyd S.
AU - Nürnberger, Thorsten
AU - LeibundGut-Landmann, Salomé
AU - Gust, Andrea A.
AU - Macek, Boris
AU - Frank, Martin
AU - Gouttefangeas, Cécile
AU - Dela Cruz, Charles S.
AU - Hartl, Dominik
AU - Weber, Alexander N.R.
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - N-acetyl-glucosamine
KW - anti-fungal innate immunity
KW - chitin
KW - inflammation
KW - toll-like receptor
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U2 - 10.15252/embr.201846065
DO - 10.15252/embr.201846065
M3 - Article
C2 - 30337494
AN - SCOPUS:85055248148
SN - 1469-221X
VL - 19
JO - EMBO Reports
JF - EMBO Reports
IS - 12
M1 - e46065
ER -