TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation

Ei’Ichi Iizasa,Hideyasu Kiyohara,Yasushi Chuma,Ikuya Yano,Hiroaki Kawaguchi,Sho Yamasaki,Hiroki Yoshida,Masahiko Sugita,Hiromitsu Hara,Marco Colonna,Takayuki Uematsu,Goro Matsuzaki,Kenji Toyonaga,Mio Kubota,Masayuki Umemura

doi:10.1038/s41467-021-22620-3

Abstract

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.

Highlights

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγassociated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9)
The surface expression of these lipids on mycobacteria masks ligands for toll-like receptors (TLRs) that are required for the induction of inducible nitric oxide synthase-positive M1-type microbicidal macrophages, and instead recruits iNOS-negative non-microbicidal macrophages to the site of infection, thereby facilitating the intracellular Mycobacterium tuberculosis (Mtb) survival and propagation[20]
We present evidence suggesting that the DAP12-associated receptor triggering receptor expressed on macrophage 2 (TREM2) recognizes mycobacterial MAcontaining lipids that are distinct from those recognized by Mincle and counteracts the Mincle–FcRγ–CARD9-mediated antimycobacterial immune response

Summary

Introduction

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγassociated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). In contrast to CLRassociated FcRγ, the other ITAM-bearing signaling adaptor, DAP12, might negatively regulate the antimycobacterial immune response, because DAP12 deficiency accelerates the clearance of mycobacteria and the granuloma formation in lungs upon Mtb or Mycobacterium bovis Bacille de Calmette et Guerin (BCG) infection[35,36]. These observations implicate unknown DAP12associated regulatory receptors that might possibly recognize immune-suppressive ligands in mycobacteria. These theoretical receptors, as well as the precise mechanisms of immune suppression via DAP12, have not been described

Methods

Results

Conclusion