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Cited by 92Tuberculosis Research and EpidemiologyImmune Response and InflammationImmune responses and vaccinations

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

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Iizasa, Ei’ichi, Chuma, Yasushi, Uematsu, Takayuki, Kubota, Mio, Kawaguchi, Hiroaki, Umemura, Masayuki, Toyonaga, Kenji, Kiyohara, Hideyasu +7 more·2021·Nature Communications
DOI 10.1038/s41467-021-22620-3PMC PMC8052348
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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.

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  • TREM2 ligands include bacterial wall products, Aβ oligomers, lipoproteins, and anionic lipids such as phospholipids and sphingolipids.

    “TREM2 ligands include a variety of molecules, such as bacterial wall products, Aβ oligomers, lipoproteins, and anionic lipids, such as phospholipids and sphingolipids29,32–35”

    From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [34]

    The Discussion (page not provided) identifies bacterial ligands and says TREM2 ligands include phospholipids and sphingolipids. It mentions apolipoproteins rather than lipoproteins, and lipids associated with fibrillar amyloid β rather than Aβ oligomers; those two parts of the claim are not supported by this copy. (LLM, conf=0.88)

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Authors
Iizasa, E., Chuma, Y., Uematsu, T., Kubota, M., Kawaguchi, H., Umemura, M., Toyonaga, K., Kiyohara, H., Yano, I., Colonna, M., Sugita, M., Matsuzaki, G., Yamasaki, S., Yoshida, H., & Hara, H.
Affiliations
  • Kagoshima University (JP)
  • Japan BCG Laboratory (JP)
  • Kitasato University Medical Center (JP)
  • Saga University (JP)
  • University of the Ryukyus (JP)
  • Osaka City University (JP)
  • Washington University in St. Louis (US)
  • Kyoto University (JP)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
Corresponding author
Hara, Hiromitsu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-16
Volume
12
Issue
1
Pages
2299-2299
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-22620-3
PMC
PMC8052348
OpenAlex
W3156612949
Cited by
92
References
105
Citations by year
2026: 13 · 2025: 30 · 2024: 19 · 2023: 10 · 2022: 18 · 2021: 2
FWCI
4.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of the Ryukyus academic repository (University of the Ryukyus) (submittedVersion, cc-by)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • University oh the Ryukyus Repository (submittedVersion, cc-by-nc-nd)
Funders
  • Takeda Science Foundation
  • NOVARTIS Foundation (Japan) for the Promotion of Science (NOVARTIS Foundation
  • Naito Foundation
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
TREM2, mycolic acids, mycobacteria, DAP12, Mincle, CARD9, FcRγ, C-type lectin receptors, macrophage activation, immune evasion, mycobacterial cell wall lipids, inducible nitric oxide synthase, mycobacterial infection, inflammation
MeSH terms
Animals, Cell Wall, Cells, Cultured, Disease Models, Animal, Female, Glycolipids, Humans, Macrophage Activation, Macrophages, Male, Membrane Glycoproteins, Membrane Proteins, Mycobacterium tuberculosis, Mycolic Acids, Receptors, Immunologic, Receptors, IgG, Mice, Knockout, Lectins, C-Type, Virulence Factors, Adaptor Proteins, Signal Transducing, Mice, CARD Signaling Adaptor Proteins, Latent Tuberculosis, Immune Evasion, Primary Cell Culture

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