Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation
Open accessAbstract
Mutations in triggering receptor expressed on myeloid cells 2 (TREM2), which has been proposed to regulate the inflammatory responses and the clearance of apoptotic neurons and/or amyloid-β, are genetically linked to increased risk for late-onset Alzheimer's disease (AD). Interestingly, a missense variant in TREM-like transcript 2 (TREML2), a structurally similar protein encoded by the same gene cluster with TREM2 on chromosome 6, has been shown to protect against AD. However, the molecular mechanisms by which TREM2 and TREML2 regulate the pathogenesis of AD, and their functional relationship, if any, remain unclear. Here, we show that lipopolysaccharide (LPS) stimulation significantly suppressed TREM2 but increased TREML2 expression in mouse brain. Consistent with this in vivo result, LPS or oligomeric amyloid-β treatment down regulated TREM2 but up-regulated TREML2 expression in primary microglia. Most important, modulation of TREM2 or TREML2 levels had opposing effects on inflammatory responses with enhancement or suppression of LPS-induced proinflammatory cytokine gene expression observed on TREM2 or TREML2 down regulation, respectively. In addition, the proliferation of primary microglia was significantly decreased when TREM2 was down regulated, whereas it was increased on TREML2 knockdown. Together, our results suggest that several microglial functions are strictly regulated by TREM2 and TREML2, whose dysfunctions likely contribute to AD pathogenesis by impairing brain innate immunity. Our findings provide novel mechanistic insights into the functions of TREM2 and TREML2 in microglia and have implications on designing new therapeutic strategies to treat AD.
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LPS/IFNγ stimulation down-regulated Trem2 expression via TLR4 receptors in cell lines and primary cultures of microglia/macrophages and also in mouse brains.
“This finding is consistent with previous studies showing that LPS/IFNγ stimulation down-regulated Trem2 expression via TLR4 receptors in cell lines and primary cultures of microglia/macrophages and also in mouse brains (14,16,42,88,89).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [88]
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“This finding is consistent with previous studies showing that LPS/IFNy stimulation down-regulated Trem2 expression via TLR4 receptors in cell lines and primary cultures of microglia/macrophages and also in mouse brains (Owens et al. 2017; Schmid et al. 2002; Turnbull et al. 2006; Zheng et al. 2016).”
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- Authors
- Zheng, H., Liu, C.-C., Atagi, Y., Chen, X.-F., Jia, L., Yang, L., He, W., Zhang, X., Kang, S. S., Rosenberry, T. L., Fryer, J. D., Zhang, Y.-W., Xu, H., & Bu, G.
- Affiliations
- Xiamen University (CN)
- Mayo Clinic in Florida (US)
- Mayo Clinic (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Bu, Guojun
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 42
- Pages
- 132-141
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4857884
- OpenAlex
- W2298610985
- Cited by
- 110
- References
- 51
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 6 · 2023: 16 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 9
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Education Department
- NIH (R01AG027924, R01AG035355, R01AG046205)
- National Natural Science Foundation (81100842, U1505227)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TREM2, microglial activation, Alzheimer's disease, lipopolysaccharide, amyloid-beta oligomers, inflammatory cytokines, microglial proliferation, innate immunity, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Immunity, Innate, Lipopolysaccharides, Membrane Glycoproteins, Mice, Inbred C57BL, Mutation, Receptors, Immunologic, Down-Regulation, Up-Regulation, Gene Expression, Cytokines, Amyloid beta-Peptides, Apoptosis, Microglia, Molecular Targeted Therapy
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