The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index.
Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
Open accessAbstract
Several genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) have been shown to increase the risk of developing Alzheimer's disease (AD) supporting a role of microglia and immune cells in the pathobiology of AD. We have employed an ectopic model of TREM2 and DAP12 expression in HEK293 cells to study selectively TREM2 dependent signaling and phagocytic functions and evaluated the effects of some of the TREM2 mutations associated with AD. We show that shedding of the TREM2 N-terminal domain does not affect the inhibition of NFκB activation induced by TREM2 while it completely blocks phagocytosis suggesting that TREM2 anti-inflammatory properties can be mediated by the TREM2 C-terminal fragment while the phagocytic activity requires the full-length receptor. In addition, we confirm in that model that apolipoprotein E (APOE) is a ligand for TREM2 and triggers TREM2 signaling. In particular, we show that APOE4 stimulates spleen tyrosine kinase (SYK) activation more potently than APOE2 in a TREM2 dependent manner. Interestingly, TREM2 appears to antagonize NFκB activation induced by phorbol ester but is unable to prevent TNFα induction of NFκB activation suggesting that TREM2 antagonizes inflammatory events triggered downstream of PKC. TREM2 mutations drastically impact TREM2 phagocytosis as well as its ability to antagonize NFκB activation and notably prevent the activation of the PI3K/AKT pathway observed with wild-type TREM2. Overall our data suggest that TREM2 dependent phagocytosis requires an activation of the SYK/PI3K/AKT/PLCγ pathways while the suppression of NFκB activation by TREM2 is independent of SYK, PI3K, and PLCγ activities. This model of ectopic TREM2-DAP12 co-expression appears suitable to study TREM2 signaling as several biological functions of TREM2 and TREM2 mutations that have been previously described in myeloid and microglial cells were also replicated in this model.
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“In addition, SYK has been identified as the central kinase that instructs signaling and effector functions downstream of TREM2, CD33, and CD22 receptors (Clark and Giltiay, 2018; Wissfeld et al., 2021; Yao et al., 2019).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Yao et al., 2019
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“Though previous in vitro studies have shown that TREM2 activation can provoke SYK signaling (Yao et al., 2019)”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Yao et al., 2019
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TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
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Metadata
- Authors
- Yao, H., Coppola, K., Schweig, J. E., Crawford, F., Mullan, M., & Paris, D.
- Affiliations
- James A. Haley Veterans' Hospital (US)
- Corresponding author
- Yao, Hailan
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2019-10-10
- Volume
- 13
- Pages
- 457-457
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC6795686
- OpenAlex
- W2979963278
- Cited by
- 110
- References
- 86
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 21 · 2023: 17 · 2022: 17 · 2021: 13 · 2020: 6
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TREM2, Alzheimer's disease, phagocytosis, NF-κB signaling, DAP12, Syk, apolipoprotein E, APOE ε4, PI3K/Akt signaling, phospholipase C-gamma, microglia, anti-inflammatory signaling, TNF-α
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