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

Ei’ichi Iizasa, Yasushi Chuma, Takayuki Uematsu, Mio Kubota, Hiroaki Kawaguchi, Masayuki Umemura, Kenji Toyonaga, Hideyasu Kiyohara, Ikuya Yano, Marco Colonna, Masahiko Sugita, Goro Matsuzaki, Sho Yamasaki, Hiroki Yoshida and Hiromitsu Hara ()
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Ei’ichi Iizasa: Kagoshima University
Yasushi Chuma: Research and Development Department, Japan BCG Laboratory
Takayuki Uematsu: Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center
Mio Kubota: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University
Hiroaki Kawaguchi: Kagoshima University
Masayuki Umemura: Tropical Biosphere Research Center, University of the Ryukyus
Kenji Toyonaga: Kagoshima University
Hideyasu Kiyohara: Research and Development Department, Japan BCG Laboratory
Ikuya Yano: Research and Development Department, Japan BCG Laboratory
Marco Colonna: BJC Institute of Health at Washington University
Masahiko Sugita: Laboratory of Cell Regulation, Institute for Virus Research, Graduate School of Biostudies, Kyoto University
Goro Matsuzaki: Tropical Biosphere Research Center, University of the Ryukyus
Sho Yamasaki: Osaka University
Hiroki Yoshida: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University
Hiromitsu Hara: Kagoshima University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22620-3

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