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

EMBO Rep. 2018 Dec;19(12):e46065. doi: 10.15252/embr.201846065. Epub 2018 Oct 18.

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.

Keywords: N‐acetyl‐glucosamine; anti‐fungal innate immunity; chitin; inflammation; toll‐like receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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