A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia
Open accessAbstract
Following neuronal injury, microglia initiate repair by phagocytosing dead neurons without eliciting inflammation. Prior evidence indicates triggering receptor expressed by myeloid cells‐2 (TREM2) promotes phagocytosis and retards inflammation. However, evidence that microglia and neurons directly interact through TREM2 to orchestrate microglial function is lacking. We here demonstrate that TREM2 interacts with endogenous ligands on neurons. Staining with TREM2‐Fc identified TREM2 ligands (TREM2‐L) on Neuro2A cells and on cultured cortical and dopamine neurons. Apoptosis greatly increased the expression of TREM2‐L. Furthermore, apoptotic neurons stimulated TREM2 signaling, and an anti‐TREM2 mAb blocked stimulation. To examine the interaction between TREM2 and TREM2‐L in phagocytosis, we studied BV2 microglial cells and their engulfment of apoptotic Neuro2A. One of our anti‐TREM2 mAb, but not others, reduced engulfment, suggesting the presence of a functional site on TREM2 interacting with neurons. Further, Chinese hamster ovary cells transfected with TREM2 conferred phagocytic activity of neuronal cells demonstrating that TREM2 is both required and sufficient for competent uptake of apoptotic neuronal cells. Finally, while TREM2‐L are expressed on neurons, TREM2 is not; in the brain, it is found on microglia. TREM2 and TREM2‐L form a receptor–ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair.
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TREM2 has many ligands, including phospholipids, sulfatides, lipoprotein particles such as HDL and LDL, and APOE.
“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 [149]
TREM2 promotes phagocytosis of apoptotic neurons, proliferation, and survival of microglia, and dampens TLR-induced inflammatory responses.
“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 [149]
TREM2 promotes proliferation, survival, and phagocytosis of apoptotic cells.
“TREM2 promotes proliferation (119), survival (119), and phagocytosis of apoptotic cells (120–122).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [120]
TREM2 functions as a cell surface receptor on microglia; via DAP12/TYROBP, TREM2 stimulation initiates signaling that promotes microglial chemotaxis, phagocytosis, survival, and proliferation.
“TREM2 functions as a cell surface receptor on microglia; via its interaction with the activating adaptor protein DAP12 (encoded by the TYROBP gene), TREM2 stimulation initiates signal transduction pathways that promote microglial chemotaxis, phagocytosis, survival, and proliferation (Takahashi et al., 2005; Hsieh et al., 2009; Kleinberger et al., 2014; Poliani et al., 2015; Wang et al., 2015, 2016”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Hsieh et al., 2009
TREM2 and TYROBP mediate phagocytosis of bacteria and apoptotic cells.
“Together, TREM2 and TYROBP mediate phagocytosis of bacteria and apoptotic cells [27, 28].”
From Microglial dysfunction in brain aging and Alzheimer's disease (2014) · cites this paper as [28]
For phagocytosis to occur, the expression of specific receptors on the microglial surface is necessary; the principal receptors are TLRs, which have high affinity for pathogens, and TREM2, which recognizes apoptotic cellular substances.
“As mentioned above, for phagocytosis to occur the expression of specific receptors on the microglial surface is necessary. The principal receptors are the TLRs, which have high affinity for pathogens, and TREM2, which recognizes apoptotic cellular substances (Hsieh et al., 2009).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Hsieh et al., 2009
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- Authors
- Hsieh, C. L., Koike, M., Spusta, S. C., Niemi, E. C., Yenari, M., Nakamura, M. C., & Seaman, W. E.
- Affiliations
- San Francisco VA Medical Center (US)
- Corresponding author
- Seaman, William E.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2009-04-14
- Volume
- 109
- Issue
- 4
- Pages
- 1144-1156
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC3087597
- OpenAlex
- W2026279003
- Cited by
- 475
- References
- 42
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 32 · 2023: 32 · 2022: 36 · 2021: 43 · 2020: 29 · 2019: 30 · 2018: 37 · 2017: 38 · 2016: 30 · 2015: 34 · 2014: 26 · 2013: 23 · 2012: 9
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH0520094, W81XWH)
- Chongqing University of Arts and Sciences
- National Institutes of Health (5f32ns060338-02, W81XWH)
- University of California, Riverside
- University of California, San Francisco
- National Institute of Neurological Disorders and Stroke (R01 NS 40516, F32 NS060338, NS 40516, R01NS040516, 5F32NS060338)
- 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, microglia, phagocytosis, neuronal injury, neuroinflammation, ligand-receptor pairs, TREM2 signaling
- MeSH terms
- Animals, Antibodies, Cell Communication, Cell Separation, Cricetulus, Cricetinae, Ligands, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Neurons, Phagocytosis, Receptors, Immunologic, RNA, Messenger, Transfection, Signal Transduction, Lentivirus, CHO Cells, Apoptosis, Microglia, Reverse Transcriptase Polymerase Chain Reaction, Myeloid Cells, Mice
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