Journal Article

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

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

2021

Overview

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. Mycobacterial cell wall lipids can drive immunoevasion, but underlying mechanisms are incompletely understood. Here the authors show TREM2 is a pattern recognition receptor that binds non-glycosylated mycolic acid-containing lipids and inhibits Mincle-induced anti-mycobacterial macrophage responses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/250/2161 / 631/250/2499 / 631/250/2504/342 / 631/250/262/2106 / 64/60 / 82/58 / 82/80 / 96/1 / 96/109 / 96/21 / 96/31 / 96/95 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / CARD Signaling Adaptor Proteins - genetics / CARD Signaling Adaptor Proteins - metabolism / Caspase / Cell activation / Cell Wall - metabolism / Cell walls / Cells, Cultured / Cytokines / DAP12 protein / Disease Models, Animal / Female / Glycolipids / Glycolipids - metabolism / Humanities and Social Sciences / Humans / Immune Evasion / Immune response / Immune system / Immunity / Inflammation / Latency / Latent Tuberculosis - immunology / Latent Tuberculosis - microbiology / Lectins, C-Type - genetics / Lectins, C-Type - metabolism / Lipids / Macrophage Activation - immunology / Macrophages / Macrophages - immunology / Male / Membrane Glycoproteins - genetics / Membrane Glycoproteins - metabolism / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, Knockout / multidisciplinary / Mycobacterium tuberculosis - immunology / Mycobacterium tuberculosis - metabolism / Mycobacterium tuberculosis - pathogenicity / Mycolic acids / Mycolic Acids - metabolism / Myeloid cells / Nitric oxide / Nitric-oxide synthase / Pattern recognition / Pattern recognition receptors / Primary Cell Culture / Receptors / Receptors, IgG - metabolism / Receptors, Immunologic - genetics / Receptors, Immunologic - metabolism / Science / Science (multidisciplinary) / Virulence / Virulence Factors - metabolism