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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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Cell Wall / metabolism
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Cells, Cultured
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Disease Models, Animal
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Female
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Glycolipids / metabolism
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Humans
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Immune Evasion*
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Latent Tuberculosis / immunology*
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Latent Tuberculosis / microbiology
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism
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Macrophage Activation / immunology
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Macrophages / immunology
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / metabolism
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Mycobacterium tuberculosis / pathogenicity
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Mycolic Acids / metabolism*
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Primary Cell Culture
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Receptors, IgG / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Virulence Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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Card9 protein, mouse
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Clecsf8 protein, mouse
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Glycolipids
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Lectins, C-Type
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Membrane Glycoproteins
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Membrane Proteins
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Mycolic Acids
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Receptors, IgG
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Receptors, Immunologic
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Trem2 protein, mouse
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Tyrobp protein, mouse
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Virulence Factors