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

TLDR

Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, whose cell‑wall glycolipid trehalose dimycolate (TDM) is a major immunostimulatory component whose host receptor had remained unidentified for decades. The study aimed to identify the host receptor for TDM and showed that macrophage‑inducible C‑type lectin (Mincle) is essential for recognizing this glycolipid. By comparing heat‑killed mycobacteria with delipidated bacteria and analyzing lipid extracts, the authors demonstrated that TDM directly binds and activates Mincle‑expressing cells. TDM induced inflammatory cytokine and nitric‑oxide production in macrophages and lung granuloma formation in vivo, effects that were abolished in Mincle‑deficient cells or mice, confirming Mincle as the critical receptor for TDM.

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.