Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle.
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.
Ishikawa
Eri
E
Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Ishikawa
Tetsuaki
T
Morita
Yasu S
YS
Toyonaga
Kenji
K
Yamada
Hisakata
H
Takeuchi
Osamu
O
Kinoshita
Taroh
T
Akira
Shizuo
S
Yoshikai
Yasunobu
Y
Yamasaki
Sho
S
D000818:Animals; D003311:Cord Factors / Q000032:analysis / Q000502:physiology*; D006099:Granuloma / Q000209:etiology; D037181:Lectins, C-Type / Q000502:physiology*; D008024:Ligands; D008171:Lung Diseases / Q000209:etiology; D008262:Macrophage Activation; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology
C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG