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Cutting Edge: Inhibition of TLR and FcR Responses in Macrophages by Triggering Receptor Expressed on Myeloid Cells (TREM)-2 and DAP12
Open accessAbstract
DAP12 is an ITAM-containing adapter that associates with receptors in myeloid and NK cells. DAP12-associated receptors can give activation signals leading to cytokine production; however, in some situations, DAP12 inhibits cytokine production stimulated through TLRs and FcRs. Here we show that Triggering Receptor Expressed on Myeloid cells (TREM)-2 is responsible for the DAP12-mediated inhibition in mouse macrophages. A chimeric receptor composed of the extracellular domain of TREM-2 and the cytoplasmic domain of DAP12 inhibited the TLR- and FcR-induced TNF production of DAP12-deficient macrophages, whereas a TREM-1 chimera did not. In wild-type macrophages, TREM-2 knockdown increased TLR-induced TNF production. A TREM-2 Fc fusion protein bound to macrophages, indicating that macrophages express a TREM-2 ligand. Thus, the interaction of TREM-2 and its ligand results in an inhibitory signal that can reduce the inflammatory response.
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“TREM2 has many ligands, including phospholipids and sulfatides, which are exposed on apoptotic or damaged cells, lipoprotein particles such as HDL and LDL, and APOE.”
From Microglia in Alzheimer's disease (2017) · cites this paper as [148]
In the citing paper
“TREM2 promotes phagocytosis of apoptotic neurons, proliferation, and survival of microglia, and has been implicated in dampening TLR-induced inflammatory responses (147-151).”
From Microglia in Alzheimer's disease (2017) · cites this paper as [148]
In the citing paper
“However, it curtails cytokine production in response to TLR ligands (122–124).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [124]
In the citing paper
“TREM2 signaling, which is protective against AD based on human genetics, curbs TLR signaling in macrophages (Hamerman et al., 2006; Turnbull et al., 2006).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Hamerman et al., 2006
In the citing paper
“Upon lipid ligand binding, TREM2 recruits SYK via DAP12’s ITAM domain, leading to SYK phosphorylation”
From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Hamerman et al., 2006
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Metadata
- Authors
- Hamerman, J. A., Jarjoura, J. R., Humphrey, M. B., Nakamura, M. C., Seaman, W. E., & Lanier, L. L.
- Affiliations
- University of California, San Francisco (US)
- San Francisco VA Medical Center (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-08
- Volume
- 177
- Issue
- 4
- Pages
- 2051-2055
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2133084626
- Cited by
- 440
- References
- 19
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 28 · 2023: 15 · 2022: 37 · 2021: 19 · 2020: 17 · 2019: 21 · 2018: 25 · 2017: 25 · 2016: 18 · 2015: 27 · 2014: 28 · 2013: 19 · 2012: 13
- FWCI
- 10.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000615)
- National Institutes of Health
- National Cancer Institute (R01CA087922, CA 87922)
- National Institute of Allergy and Infectious Diseases (AI-068129, R01AI068129)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050038, AR 050038)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, DAP12, macrophages, Toll-like receptor signaling, Fc receptor signaling, TNF production, inhibitory signaling, TREM-1, chimeric receptors, cytokine production, inflammation regulation
- MeSH terms
- Animals, Cells, Cultured, Ligands, Macrophages, Membrane Glycoproteins, Mice, Inbred C57BL, Receptors, Fc, Receptors, Immunologic, Tumor Necrosis Factor-alpha, Mice, Knockout, Inflammation Mediators, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Mice
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