Ei'ichi Iizasa1, Yasushi Chuma2, Takayuki Uematsu3, Mio Kubota4, Hiroaki Kawaguchi5, Masayuki Umemura6, Kenji Toyonaga1,7, Hideyasu Kiyohara2, Ikuya Yano2,8, Marco Colonna9, Masahiko Sugita10, Goro Matsuzaki6, Sho Yamasaki7, Hiroki Yoshida4, Hiromitsu Hara11. 1. Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. 2. Research and Development Department, Japan BCG Laboratory, Tokyo, Japan. 3. Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama, Japan. 4. Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan. 5. Department of Hygiene and Health Promotion Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. 6. Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan. 7. Department of Molecular Immunology, Division of Host Defense, Research Institute for Microbial Disease, Osaka University, Osaka, Japan. 8. Faculty of Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. 9. Department of Pathology and Immunology, BJC Institute of Health at Washington University, St. Louis, MO, USA. 10. Laboratory of Cell Regulation, Institute for Virus Research, Graduate School of Biostudies, Kyoto University, Kyoto, Japan. 11. Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. harah@m2.kufm.kagoshima-u.ac.jp.
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.
Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, inpan class="Gene">cluding 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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