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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SYK is the central kinase that instructs signaling and effector functions downstream of TREM2, CD33, and CD22 receptors.
“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
The Introduction (page unavailable) describes SYK as a proposed key kinase in TREM2 signaling. The Results section on SYK-dependent phagocytosis (page unavailable) finds that SYK only partially mediates TREM2 phagocytosis and is not required for its suppression of NFκB activation. The paper does not establish the claimed role downstream of CD33 or CD22. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPrevious in vitro studies have shown that TREM2 activation can provoke SYK signaling.
“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 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
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SYK coordinates neuroprotective microglial responses in neurodegenerative disease
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“Though previous in vitro studies have shown that TREM2 activation can provoke SYK signaling (Yao et al., 2019), it still remains to be seen whether TREM2 relies exclusively on SYK to coordinate its effects on in vivo Alzheimer’s-related disease progression.”
BackgroundTrem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis
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Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review
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TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
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A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
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Present and future of microglial pharmacology
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Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability—Brief Report
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Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
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TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells
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Microglia, Trem2, and Neurodegeneration
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ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
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The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells
Cai, W., Wu, T., & Chen, N. (2023) · Biomolecules · doi:10.3390/biom13020313 · Cited by 65 · see citing works
Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma
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TREM2 Promotes Immune Evasion by Mycobacterium tuberculosis in Human Macrophages
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Crosstalk between Microglia and Neurons in Neurotrauma: An Overview of the Underlying Mechanisms
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The Functions and Phenotypes of Microglia in Alzheimer’s Disease
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Microglia-mediated neuroinflammation in traumatic brain injury: a review
Obukohwo, O. M., Oreoluwa, O. A., Andrew, U. O., & Williams, U. E. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09995-4 · Cited by 47 · see citing works
A multi‐hit hypothesis for an <i>APOE4</i> ‐dependent pathophysiological state
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Canonical and Noncanonical Autophagy Pathways in Microglia
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The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention
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Variant TREM2 Signaling in Alzheimer's Disease
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TREM2, microglial and ischemic stroke
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Microglial autophagy in Alzheimer’s disease and Parkinson’s disease
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Roles of TREM2 in Alzheimer’s disease
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Impaired microglial phagocytosis promotes seizure development
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Microglial dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions
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Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models
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Microglia‐derived extracellular vesicles in homeostasis and demyelination/remyelination processes
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Alzheimer’s Disease Genetics: A Dampened Microglial Response?
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Survival motor neuron protein deficiency alters microglia reactivity
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INPP5D/SHIP1: Expression, Regulation and Roles in Alzheimer’s Disease Pathophysiology
Olufunmilayo, E. O., & Holsinger, R. M. D. (2023) · Genes · doi:10.3390/genes14101845 · Cited by 19 · see citing works
Adrenal gland macrophages regulate glucocorticoid production through Trem2 and TGF-β
Xu, Y., Patterson, M. T., Dolfi, B., Zhu, A., Bertola, A., Schrank, P. R., Gallerand, A., Kennedy, A. E., Hillman, H., Dinh, L., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.174746 · Cited by 20 · see citing works
Syk inhibitors protect against microglia-mediated neuronal loss in culture
Birkle, T. J. Y., & Brown, G. C. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1120952 · Cited by 15 · see citing works
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Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation
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Synergistic reduction in interfacial flexibility of TREM2 R47H and ApoE4 may underlie AD pathology
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The triggering receptor expressed on myeloid cells 2–apolipoprotein E signaling pathway in diseases
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Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration
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Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression
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TREM2 in Regulating Macrophage Inflammatory Responses and Disease Pathogenesis
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The role of DAP12 in immune-related inflammatory diseases
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Visualising the Knowledge Structure of Microglia in Alzheimer’s Disease: A CiteSpace Analysis
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TREM2 as a possible link between Alzheimer's disease and diabetes mellitus
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- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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