Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle

Eri Ishikawa, Tetsuaki Ishikawa, Yasu S. Morita, Kenji Toyonaga, Hisakata Yamada, Osamu Takeuchi, Taroh Kinoshita, Shizuo Akira, Yasunobu Yoshikai, Sho Yamasaki

Research output: Contribution to journalArticlepeer-review

482 Citations (Scopus)

Abstract

Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6′-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are completely suppressed in Mincle-deficient macrophages. In vivo TDM administration induced a robust elevation of inflammatory cytokines in sera and characteristic lung inflammation, such as granuloma formation. However, no TDM-induced lung granuloma was formed in Mincle-deficient mice. Whole mycobacteria were able to activate macrophages even in MyD88-deficient background, but the activation was significantly diminished in Mincle/MyD88 double-deficient macrophages. These results demonstrate that Mincle is an essential receptor for the mycobacterial glycolipid, TDM.

Original languageEnglish
Pages (from-to)2879-2888
Number of pages10
JournalJournal of Experimental Medicine
Volume206
Issue number13
DOIs
Publication statusPublished - Dec 21 2009

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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