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TREM2-Ligand Interactions in Health and Disease
Open accessAbstract
The protein triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer's disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases and the recent advances in our understanding of TREM2 and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.
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“TREM2 binds lipids exposed on the surface of apoptotic cells [49, 50], as well as ApoE [51] and lipidated Amyloid beta (Aβ) [52].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [52]
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“TREM2 associates with the immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptor protein DAP12 to induce signal transduction, including recruitment and activation of spleen tyrosine kinase (SYK) and calcium flux24,25.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [24]
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Cites
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BackgroundInfluentialVariant of TREM2 Associated with the Risk of Alzheimer's Disease
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“The importance of TREM2 is highlighted by genetic studies linking TREM2 variants to various neurodegenerative diseases, including Alzheimer’s disease (AD) [4, 5].”
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“RNA expression analyses have confirmed Trem2 is expressed selectively on microglia in the brain [40, 41], and parabiosis experiments show these microglia are most likely resident microglia and not infiltrating monocytes [42], although this is still controversial [43].”
Background
Flagged first, then by citations
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Items 101–200 of 241
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“These results suggest that TREM2 and CSF1R are in close physical proximity (6).”
BackgroundInsights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2
Coelho, I., Duarte, N., Macedo, M. P., & Penha‐Gonçalves, C. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061248 · Cited by 23
“In addition, Trem-2 has been shown to bind a wide array of anionic molecules such as bacterial products, DNA, and lipoproteins [87].”
BackgroundIjaz, A., Yarlagadda, B. R. G., & Orecchioni, M. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1589629 · Cited by 26
“TREM2 is associated with multiple disease conditions and functions, including diabetes, apoptosis, central nervous system dysfunction, and in fl ammation (106 – 109).”
Factors influencing phagocytosis of malaria parasites: the story so far
Chua, C. L., Ng, I., Yap, B. J. M., & Teo, A. (2021) · Malaria Journal · doi:10.1186/s12936-021-03849-1 · Cited by 23
Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models
Manich, G., Gómez‐López, A. R., Almolda, B., Villacampa, N., Recasens, M., Shrivastava, K., González, B., & Castellano, B. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.567404 · Cited by 27
Li, Y., Jiang, J. H., Tang, Q., Tian, H., Wang, S., Wang, Z., Liu, H., Yang, J., & Ren, J. (2020) · Neural Plasticity · doi:10.1155/2020/8867547 · Cited by 20
“Studies have implicated that the amyloid β-protein in the pathogenesis of AD was associated with the endogenous ligand of TREM2 [36, 37].”
BackgroundTREM2 in Neurodegenerative Disorders: Mutation Spectrum, Pathophysiology, and Therapeutic Targeting
Yang, H.-W., Kim, D., Yang, Y., Bagyinszky, E., & An, S. S. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157057 · Cited by 26
“Moreover, Toll-like receptors (TLRs) can detect pathogen-related molecular patterns to trigger inflammatory responses, whereas TREM2 contributes to neuroprotection by regulating these inflammatory processes [19–25].”
InfluentialZhu, B., Feng, J., Liang, X., Fu, Z., Liao, M., Deng, T., Wang, K., Xie, J., Chi, J., Yang, L., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02538-1 · Cited by 24
“In the central nervous system, TREM2 is mainly expressed in microglia, which have been shown to clear the misfolded and aggregated α -Syn in PD [7], participating in the proliferation, phagocytosis, survival, and expression of in fl ammatory factors in microglia [8].”
Liu, C., & Zhou, X. (2024) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-024-01520-5 · Cited by 22
“Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor encompassing a single immunoglobulin-superfamily domain widely expressed on myeloid cells, such as immature dendritic cells, osteoclasts, tissue macrophages, and microglia [5].”
Current understanding on TREM-2 molecular biology and physiopathological functions
Bharadwaj, S., Groza, Y., Mierzwicka, J. M., & Malý, P. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112042 · Cited by 23
Zhang, X., Chen, X., Zhang, L., Sun, Y., Liang, Y., Li, H., & Zhang, Y. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105639 · Cited by 23
He, C., Liu, R., Fan, Z., Li, Y., Yang, M., Wugang, H., Lu, Z., Fang, Z., & Su, B. (2021) · Pain and Therapy · doi:10.1007/s40122-021-00288-3 · Cited by 28
“In the nervous system, it is mostly expressed in microglia, with a small amount expressed in astrocytes and neurons [33, 34].”
BackgroundThe double-edged role and therapeutic potential of TREM2 in atherosclerosis
Zhu, B., Liu, Y., & Peng, D. (2024) · Biomarker Research · doi:10.1186/s40364-024-00675-w · Cited by 28
“Notably, the signaling pathways mediated by TREM2 and their functions may differ in various cell types or under different physiological or pathological conditions [18].”
BackgroundNew insights into SYK targeting in solid tumors
Joshi, S. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.08.006 · Cited by 25
Liu, H., Zhang, L., Liu, Z., Lin, J.-Y., He, X.-J., Wu, S., Qin, Y., Zhao, C., Guo, Y., & Lin, F. (2023) · iScience · doi:10.1016/j.isci.2023.107496 · Cited by 20
TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential
Li, L., Zheng, X., Ma, H., Zhu, M., Li, X., Sun, X., & Feng, X. (2025) · Cells · doi:10.3390/cells14171387 · Cited by 22
“…ligand interactions through three primary mechanisms: (1) pattern recognition of bacterial components (e.g., lipopolysaccharide); (2) phospholipid sensing via phosphatidylserine binding; and (3) molecular chaperone interactions with apolipoproteins, including Apolipoprotein E (APOE) [24,25].”
TREM2-expressing macrophages in liver diseases
Wang, X., Qiu, Z., Zhong, Z., & Liang, S. (2025) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2025.04.009 · Cited by 24
Microglial and TREM2 dialogues in the developing brain
Morini, R., Tagliatti, E., Bizzotto, M., & Matteoli, M. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.022 · Cited by 24
Lin, C., Kong, Y., Chen, Q., Zeng, J., Pan, X., & Miao, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1420731 · Cited by 24
“…in a spectrum of functions, particularly evident during the early stages of AD, where its accumulation around damaged neurons and protein plaques suggests a role in initiating innate immune responses and potentially exacerbating the disease state (Kober and Brett, 2017; Song et al., 2018).”
BackgroundBasha, S. C., Ramaiah, M. J., & Rao, K. S. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221070 · Cited by 23
“The shedding of the ectodomain portion of TREM2 is promoted by various ligands [29].”
BackgroundInfluentialThe versatile role of TREM2 in regulating of microglia fate in the ischemic stroke
Ma, W.-Y., Wang, S., Wu, Q.-L., Zhou, X., Chu, S., & Chen, N. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108733 · Cited by 20
D’Oliveira Albanus, R., Finan, G. M., Brase, L., Sweeney, N., Kim, T. Y., Chen, S., Ryoo, Y., Park, J., Guo, Q., Iyer, A. K., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adx0027 · Cited by 19
Nagy, G., Bojcsuk, D., Tzerpos, P., Cseh, T., & Nagy, L. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae088 · Cited by 17
“In addition, our list includes several genes involved in bacterial pattern recognition ( Cd14 , Trem2 ) ( 81 ,82 ) or antiviral response ( Irf5 , Isg15 , Ifi203 , Ly6e ) ( 83–86 ), as well as those encoding chemokines ( Ccl3 , Ccl4 , Ccl9 ) ( 87 ) or macrophage-specific proteases ( Lyz2 , Mmp12 ,…”
Shan, S., Chao, S., Liu, Z., Wang, S., Liu, Z., Zhang, C., Cheng, D., Su, Z., & Song, F. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.05.004 · Cited by 17
TREM2 in cardiovascular diseases: Mechanisms and therapeutic perspectives
Zhu, W., Yue, Z., Wang, Y., Guo, L., & Liu, C. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102774 · Cited by 18
“TREM2 recognizes diverse ligands associated with tissue damage, neurodegeneration, and metabolic dysregulation (Bharadwaj et al., 2024; Deczkowska et al., 2020; Singh et al., 2021; Kober et al., 2017).”
Yu, J.-B., Hong, C., Ren, X.-W., Guo, W., Chen, Y.-F., Ji, J., Zhang, X., & Sun, X. (2025) · Stroke · doi:10.1161/strokeaha.124.049745 · Cited by 23
TREM2 in neurodegeneration and diseases
Abdulkhaliq, A. A., Alasiri, G., Kim, B., Khan, J., Ajoolabady, A., Yousof, S. M., Ren, J., Tuomilehto, J., Borai, A., Alrfaei, B. M., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03505-7 · Cited by 16
Wei, W., Qu, Z.-L., Li, L., & Zhang, P. (2024) · Current Medical Science · doi:10.1007/s11596-024-2946-3 · Cited by 17
“For example, during bacterial infection, when tissue injury and pathogen penetration occur concurrently, TREM2 binds bacterial anionic compounds such as lipopolysaccharides and dextran sulfates, as well as cellular fragments via different surface phospholipids and glycolipids [15] .”
Multimerization of TREM2 is impaired by Alzheimer's disease–associated variants
Dean, H. B., Greer, R. A., Yang, S., Elston, D. S., Brett, T. J., Roberson, E. D., & Song, Y. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14124 · Cited by 20
Self-citationHan, S., Li, X., Xia, N. L., Zhang, Y., Yu, W., Li, J., Jiao, C., Wang, Z., & Pu, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076348 · Cited by 16
“Trem2 is a transmembrane protein that can recognize a variety of ligands, including DNA and lipoproteins [8,9], and was previously found to transmit intracellular signals that maintain microglial responses during Alzheimer’s disease.”
BackgroundHypoxia/ischemia impairs CD33 (Siglec-3)/TREM2 signaling: Potential role in Alzheimer's pathogenesis
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105186 · Cited by 20
“The activation mechanisms of the TREM2/DAP12 complex and its signaling pathways have been described in detail in excellent review articles (Jay et al., 2017; Kober and Brett, 2017; Deczkowska et al., 2020).”
Differential interaction with TREM2 modulates microglial uptake of modified Aβ species
Joshi, P., Riffel, F., Satoh, K., Enomoto, M., Qamar, S., Scheiblich, H., Villacampa, N., Kumar, S., Theil, S., Parhizkar, S., et al. (2021) · Glia · doi:10.1002/glia.24077 · Cited by 21
“TREM2 binds anionic ligands, including certain phospholipids and apolipoproteins (Bailey et al., 2015; Kober & Brett, 2017; Yeh et al., 2016).”
BackgroundMishra, S., Swain, P. S., Pati, S., & Dehury, B. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e41414 · Cited by 14
Yang, Y., Shi, G., Ge, Y., Huang, S., Cui, N., Tan, L., Liu, R., & Yang, X. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03314-1 · Cited by 16
“Some ligands, such as lipoproteins, phospholipids and Aβ, are able to bind to TREM2 [29], wherein Aβ contacts TREM2 to induce microglial phagocytosis of Aβ in a spleen tyrosine kinase (SYK)-dependent manner [25, 30].”
Pramanik, S., Harini Devi, M., Chakrabarty, S., Paylar, B., Pradhan, A., Thaker, M., Ayyadhury, S., Manavalan, A., Olsson, P., Pramanik, G., et al. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105834 · Cited by 18
TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features
Samanci, B., Bilgiç, B., Gelişin, Ö., Tepgeç, F., Guven, G., Tüfekçioğlu, Z., Alaylıoğlu, M., Hanagasi, H. A., Gürvit, H., Guerreiro, R., et al. (2021) · European Journal of Neurology · doi:10.1111/ene.14908 · Cited by 14
“TREM2 signaling remains poorly understood and receptor– ligand interactions are complex as there are a variety of ligands of TREM2 receptor such as lipoproteins (low- density lipoprotein) and apolipoproteins (APOE), and bacterial anionic molecules [37,38].”
BackgroundMatejuk, A., Matejuk, S., Offner, H., & Vandenbark, A. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178314 · Cited by 14
“TREM2 is a central hub in the innate immune response and has been found to be activated by various proteins and lipids [68].”
Richard, S. A. (2022) · Journal of Oncology · doi:10.1155/2022/8903482 · Cited by 15
In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages
Hall‐Roberts, H., Daniel, E. D., James, W., Davis, J. B., & Cowley, S. A. (2021) · Journal of Visualized Experiments · doi:10.3791/62217 · Cited by 13
Kurakin, A. V., & Bredesen, D. E. (2020) · Aging · doi:10.18632/aging.103883 · Cited by 15
“important roles in chronic obstructive pulmonary disease (COPD), gut injury, and infections [154].”
BackgroundSynthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases
Dong, X., Zhao, X., Gao, J., Bo, L., Li, Y., Kong, Z., 孙维绎, Xu, X., Liu, Z., Xiu, Q., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102580 · Cited by 7
“As TREM2 has been reported to promote macrophage proliferation and survival, 6 we next examined whether CRT could exert a similar effect.”
Synergistic reduction in interfacial flexibility of TREM2 R47H and ApoE4 may underlie AD pathology
Lietzke, E. E., Saeb, D., Aldrich, E. C., Bruce, K. D., & Sprenger, K. G. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70120 · Cited by 16
Qi, W., Ma, M., Yu, H., Yu, H., Zhang, S., & Li, R. (2021) · Bioengineered · doi:10.1080/21655979.2021.2009971 · Cited by 13
“TREM2 signaling is involved in cell activation, survival, inflammation, regulation, and phagocytosis [29].”
BackgroundRetractedAs48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition
Cho, S., Gaamouch, F. E., Upadhyay, S., Nada, H., Kuncewicz, K., & Gabr, M. T. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118862 · Cited by 15
Li, J., Yu, X., Yang, D., Chen, S., Xu, J., Ma, S., Huang, C., Xu, B., Xue, L., & Wang, Y. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10250-1 · Cited by 10
“Given the diversity of TREM2 ligands and the resulting complexity of its signaling pathways, TREM2’s function likely varies significantly across different cell types (Kober and Brett 2017 ).”
Wang, M., Zhao, R., Su, Y., Zhai, D., Liang, H., Zhang, L., Wang, W., Wang, Z., Qi, M., Jiang, X., et al. (2025) · Inflammation · doi:10.1007/s10753-025-02279-4 · Cited by 8
“Recently, TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been identified as a unidirectional transmembrane receptor predominantly found on microglia and myeloid cells [20].”
Thu, V. T. A., Hoang, T. X., & Kim, J. Y. (2023) · BioMed Research International · doi:10.1155/2023/3483411 · Cited by 12
“Ectodomain of TREM2 binds to a variety of ligands, including bacterial polysaccharides, lipoproteins, phospholipids, and DNA [13].”
BackgroundTREM-2: friend or foe in infectious diseases?
Matos, A. D. O., Dantas, P. H. D. S., Queiroz, H. A. G. D. B., Silva‐Sales, M., & Sales‐Campos, H. (2022) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2022.2146481 · Cited by 12
“…a V-type immunoglobulin domain (amino acids [aa] 1-172), a transmembrane domain (aa 173 – 95) and a short cytoplasmic tail (aa 196 (cid:1) 230) that lacks immunoreceptor tyrosine-based activation motifs (ITAMs) (Kober and Brett 2017; Dean et al. 2019; Deczkowska et al. 2020; Yang et al. 2020).”
BackgroundInfluentialDecoding of the Role of TREM2 in Neuropathic Pain: Molecular Pathway and Neuroinflammatory Mechanism
Vijayan, N., Veeraveedu, P. T., & Patel, S. (2025) · Drug Development Research · doi:10.1002/ddr.70111 · Cited by 10
“Structurally, TREM2 comprises a single V ‐ type immunoglobulin ‐ like domain, an isolated ecto-domain, a transmembrane helix, and a short cytoplasmic tail lacking intrinsic motifs for trafficking or signal transduction (Kober and Brett 2017).”
McMillan, I. O., Liang, L., Su, G., Song, X., Drago, K., Yang, H., Alvarez, C., Sood, A., Gibson, J. M., Woods, R. J., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107691 · Cited by 11
“TREM2 plays a vital role in regulating in-fl ammatory responses, phagocytosis, cell survival, and neuro-protection (1 – 3).”
BackgroundSelf-citationZhong, Z., Ulmschneider, M. B., & Lorenz, C. D. (2024) · ACS Omega · doi:10.1021/acsomega.4c03060 · Cited by 8
Hu, H., Ma, L., Hu, H., Bi, Y., Ma, Y., Shen, X., Ou, Y., Dong, Q., Tan, L., & Yu, J. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00383-5 · Cited by 11
Lin, D., Kaye, S. D., Chen, M., Lyanna, A., Ye, L., Hammond, L. A., & Gao, J. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107874 · Cited by 12
“TREM2 R47H variant impairs the af fi nity of TREM2 for its ligands, resulting in a 3-to 4-fold increased risk of developing AD (3, 4).”
Tang, S., Xing, W.-L., Yan, J., Wang, L., Li, Z., Wang, Y., Gu, N., & Sun, X.-C. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149235 · Cited by 9
Arsenault, R., Marshall, S., Salois, P., Li, Q., & Zhang, W. (2024) · Biology · doi:10.3390/biology13020087 · Cited by 11
“Under normal physiological conditions TREM2 signaling is shown to recruit and phosphorylate Syk enzyme to communicate downstream after ligand binding and association with its adaptor protein DAP12 [2,7,10] Piceatannol was used to treat THP-1 cells at an IC50 of 15 µ M (Figure 6A).”
BackgroundMethodThe Pathogenesis in Alzheimer's Disease: TREM2 as a Potential Target
Liu, G., Zhang, L., Fan, Y., & Ji, W. (2023) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2206150 · Cited by 13
“Genetic variations in TREM2 have been linked to several neurodegenerative diseases [121,122].”
BackgroundAlbanus, R. D., Finan, G. M., Brase, L., Chen, S., Guo, Q., Kannan, A., Acquarone, M., You, S.-F., Novotny, B., Pereira, P. M. R., et al. (2023) · bioRxiv · doi:10.1101/2022.11.11.516215 · Cited by 9
“The role of SEMA6D in immune 476 activation was described in a study showing that SEMA6D induces activation of bone marrow477 derived macrophages in a TREM2- and PLXNA1-dependent manner via the activation of 478 DAP12, consistent with the formation of a complex (28, 52, 53).”
Emerging non-proinflammatory roles of microglia in healthy and diseased brains
Sun, Y., Che, J., & Zhang, J. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110664 · Cited by 10
“a variety of ligands including multiple anions, lipids, amyloid β (Aβ), and apolipoproteins (Daws et al., 2003; Kober and Brett, 2017; Zhao et al., 2018).”
BackgroundWhat Is the Role of Microglial Metabolism in Inflammation and Neurodegeneration?
Benarroch, E. E. (2022) · Neurology · doi:10.1212/wnl.0000000000200920 · Cited by 10
“The triggering receptor expressed on myeloid cells (TREM2) is exclusively expressed in microglia and binds multiple ligands that regulate microglial activation.(8,9) In response to environmental stimuli, microglia switch into a reactive state, altering their transcriptome programming and acquiring different activation…”
BackgroundHolloway, O. G., King, A. E., & Ziebell, J. M. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200098 · Cited by 10
“ligation of immunoglobulin Fc gamma receptors 637 (Fc Rs), resulting in downregulated expression of 638 IL-12 and increased IL-10 and HLA-DR expression, 639 while TREM2 is associated with a wide array of 640 functions in the healthy CNS, such as survival, activa641 tion, proliferation, phagocytosis, cell maturation, a…”
Genetic intolerance analysis as a tool for protein science
Li, G., Forster-Benson, E. T. C., & Sanders, C. R. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2019.183058 · Cited by 10
Liao, Y., Mu, G., Deng, S., Lu, B. F., & Zheng, M. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07604-x · Cited by 8
Nada, H., Yuan, S., Gaamouch, F. E., Cho, S. W., Kuncewicz, K., Calvo‐Barreiro, L., & Gabr, M. T. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118358 · Cited by 11
Building a potent TREM2 agonistic, biparatopic, common light chain antibody
Almeida, A. R., Geddie, M. L., Bhate, A., Quan, C., Arndt, J. W., Jiao, Y., Santoro, J. C., Noiman, L., Vijayakumar, R., Sanchez-Salazar, J., et al. (2025) · mAbs · doi:10.1080/19420862.2025.2546554 · Cited by 8
“To produce the AsBs biparatopic antibody format, we combined non-crossblocking antibodies 3 or 4 with antibody 10 and used controlled Fab arm exchange (cFAE) mutations to facilitate production from purified parental mAbs.”
Alí‐Ruiz, D., Vitureira, N., & Peluffo, H. (2023) · Scientific Reports · doi:10.1038/s41598-023-43840-1 · Cited by 8
Subramanian, A., Vernon, K. A., Zhou, Y., Marshall, J. L., Alimova, M., Zhang, F., Slyper, M., Waldman, J., Montesinos, M. S., Dionne, D. A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.30.446342 · Cited by 14
“Among several reported TREM2 ligands (Kober and Brett, 2017), only SEMA6D, expressed in podocytes, PECs, glia, and a number of distal tubular epithelial cells (tDL, DCT, TAL, CD-PC, CD-A-IC) crossed the prevalence threshold.”
BackgroundLizcano, F., Sanabria, D., & Aviles, E. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1622186 · Cited by 8
Liu, S., Dong, Y., Zhang, X., Pan, X., Wang, R., Ma, H., Sun, N., & Cao, X. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.05.417 · Cited by 8
Que, X., Zhang, T., Liu, X. Y., Yin, Y., Xia, X., Gong, P., Song, W., Qin, Q., Xu, Q., & Tang, Y. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102732 · Cited by 8
“Physiologically, TREM2 can bind to various anionic molecules within myelin, including sphingo-myelin, cerebrosides, fatty acids, and phosphatidylcholine (PC), allowing it to “ monitor ” the health status of myelin in real-time (Kober and Brett, 2017; Li et al., 2022).”
Santol, J., Rajcic, D., Ortmayr, G., Hoebinger, C., Baranovskyi, T. P., Rumpf, B., Schuler, P., Probst, J., Aiad, M., Kern, A. E., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101226 · Cited by 7
“31 34 In the central nervous system, TREM2 is mainly expressed on microglia/macrophages.”
Abe, Y., Spann, N. J., Tang, W., Zeng, F., Seymour, C., Jansky, S., Guo, J. L., Huff, R. M., Chanthavixay, K., Richard, J. L. C., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02217-4 · Cited by 7
“TREM2 binds a variety of ligands, including phosphatidylserine and phosphatidylcholine, which are exposed on dying cells 31 .”
Xiao, Y., Chen, Y., Huang, S., He, H., Hu, N., Lin, S., & You, Z. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.02.045 · Cited by 9
Coupling of Alzheimer’s Disease Genetic Risk Factors with Viral Susceptibility and Inflammation
Cao, C., Fu, G., Xu, R., & Li, N. (2023) · Aging and Disease · doi:10.14336/ad.2023.1017 · Cited by 8
“A variety of ligands can bind to TREM2, including lipoproteins, phospholipids, DNA, apoptotic cells, and bacterial products [117].”
BackgroundThe Role of TREM2 After Stroke: From Mechanisms to Therapeutic Potential
Zhou, T., Chen, A., Sun, Y., Huang, B., Xu, Y., & He, Q. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05622-w · Cited by 6
“These ligands include lipoproteins, nucleic acids, microbial elements, and phospholipids [5].”
InfluentialZhang, M., Xie, J.-G., Ma, Y.-X., Wang, L.-X., Liu, L., Zhang, P., Dai, Z., Zhang, Q., & Yin, W. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05796-5 · Cited by 6
“③ Long-term neurodegeneration: Chronic TNF-α exposure leads to tau protein hyperphosphorylation and β-amyloid deposition [ 57], both of which are closely associated with post-traumatic neurodegenerative pathologies [75].”
Boreland, A. J., Abbo, Y., Li, X.-D., Stillitano, A. C., Zhang, S.-W., Duan, J.-B., Pang, Z.-P. P., & Hart, R. P. (2025) · bioRxiv · doi:10.1101/2025.08.04.668469 · Cited by 6
“Importantly, due to the affinity of this receptor for lipid-31 associated complexes such as myelin and beta amyloid, TREM2 is believed to play an important role in AD onset and progression 26 .”
Yagi, H., Boeck, M., Neilsen, K., Yang, J., Ko, M., Tomita, Y., Negishi, K., Fu, Z., Sun, Y., & Smith, L. E. H. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.321809 · Cited by 6
Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer
Zheng, W., Yu, W., Hua, R., He, J., Wu, N., Tian, S., Huang, W., & Qin, L. (2024) · Translational Cancer Research · doi:10.21037/tcr-24-201 · Cited by 6
“Triggering receptor expressed on myeloid cells 2 (TREM2) is mainly expressed on cells such as macrophages (including osteoclasts and microglia) and dendritic cells (DCs) (4).”
Malhi, N. K., Luo, Y., Tang, X., Chadha, R. S., Tapia, A., Yuan, D., Yin, S., Liu, X., Chen, M., Qi, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.14.594235 · Cited by 7
“To date, several putative TREM2 ligands across different tissues have been identified and the repertoire continues to grow (69).”
Timmerman, R., Zuiderwijk-Sick, E. A., Oosterhof, N., Jong, A. E. J. '., Veth, J., Burm, S. M., van Ham, T. J., & Bajramovic, J. J. (2021) · Glia · doi:10.1002/glia.24136 · Cited by 6
“Importantly, we observed that microglial signature genes C1QC, CX3CR1, GPR34, HEXB, P2RY12, P2RY13, and TREM2 were significantly upregulated in spheres as compared to microglia monocultures (Figure 5e).”
BackgroundInfluentialPissarek, M. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12100925 · Cited by 6
A Photoactivatable Free Mycolic Acid Probe to Investigate Mycobacteria–Host Interactions
Agu, K. C., Banahene, N., Santamaria, C., Kim, C. Y., Cabral, J., Biegas, K. J., Papson, C., Kruskamp, A. D., Siegrist, M. S., & Swarts, B. M. (2025) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.5c00068 · Cited by 5
Bano, N., Khan, S., Ahamad, S., Dar, N. J., Alanazi, H. H., Nazir, A., & Bhat, S. A. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00617 · Cited by 6
TREM2 as a Therapeutic Target in Atherosclerosis
Xu, S., Yang, B., Yu, W., Gao, Y., Cai, H., & Wang, Z. (2025) · Cell Biology International · doi:10.1002/cbin.12279 · Cited by 7
Substrate Selection Criteria in Regulated Intramembrane Proteolysis
Moser, C., Guschtschin-Schmidt, N., Silber, M., Flum, J., & Muhle‐Goll, C. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00068 · Cited by 5
Protein recognition is chiefly mediated by the CDR2 region in TREM2 - an in silico characterization
Dantas, P. H. D. S., Matos, A. D. O., Colmenares, M. T. C., Costa, V. A. F., Felice, A. G., Neto, J. R. D. C., Soares, S. D. C., Silva‐Sales, M., Neves, B. J., & Sales‐Campos, H. (2025) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2025.109058 · Cited by 4
Bibliometric Analysis of TREM2 (2001-2022): Trends, Hotspots and Prospects in Human Disease
Qian, M., Zhong, J., Lu, Z., Zhang, W., Weng, M., Zhang, K., & Jin, Y. (2024) · International Journal of Medical Sciences · doi:10.7150/ijms.96851 · Cited by 4
“TREM2 interacts with a variety of anionic molecules that serve as ligands, including bacterial components, neuronal cells, bone marrow-derived macrophages, apoptotic cells, and apolipoproteins (A, B, E, and J) [2].”
BackgroundTotal Chemical Synthesis of Glycosylated TREM2 Ectodomain
Wijegunawardena, G., Castillo, E., Henrickson, B., Davis, R., Condello, C., & Wu, H.-F. (2023) · bioRxiv · doi:10.1101/2023.04.14.536909 · Cited by 4
TREM2 coding variants in Slovak Alzheimer's disease patients
Ďurmanová, V., Javor, J., Párnická, Z., Minárik, G., Ocenasova, A., Vašečková, B., Kiralyova, I., Šutovský, S., Petrovič, R., & Shawkatová, I. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2104105 · Cited by 5
“Regarding the TREM2 R62H variant its decreased ligand affinity has been observed [9].”
BackgroundTREM2 R47H exacerbates immune response in Alzheimer’s disease brainPreprint
Korvatska, O., Kiianitsa, K., Ratushny, A., Matsushita, M., Beeman, N., Chien, W.-M., Satoh, J.-I., Dorschner, M., Keene, C., Bammler, T., et al. (2018) · bioRxiv · doi:10.1101/499319 · Cited by 4
“mutations alter the ligand-binding interface of TREM2 (54, 55).”
BackgroundTanaka, M., Yamakage, H., Inoue, T., Masuda, S., Ohue-Kitano, R., Kusakabe, T., & Satoh-Asahara, N. (2017) · doi:10.4172/2161-0460.1000380 · Cited by 4
“In this respect, recent studies uncovered sTREM2 as not just an inactive end-product but also a signaling molecule [15] that promotes macrophage survival by preventing apoptosis [32] and activates microglia to ultimately trigger inflammatory responses and prolong survival [33].”
BackgroundWang, H., Wen, R., Parker, E., & Yang, L. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03083-9 · Cited by 2
“By competitively binding ligands, sTREM2 acts as a decoy receptor to modulate ligand availability for membrane-anchored TREM2 [106, 107].”
Hou, K., An, Z., Xu, Y., Wang, J., Zhou, M., Liu, Y., Zhu, X., & Wei, J. (2026) · npj Parkinson s Disease · doi:10.1038/s41531-025-01247-x · Cited by 5
“Structural biology and omics studies have con fi rmed that TREM2 can interact with a variety of signaling molecules, including phospholipids, lipoproteins, components of apoptotic cells, lipid metabolites, and damage-associated molecular patterns 71,89,90 .”
Akinluyi, E. T., Takahashi, K., Connolly, M. G., Poon, W. W., & Macauley, M. S. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00805 · Cited by 5
Peng, B., Liu, K., Xiang, X., Zhang, Y.-F., Li, H., Zhang, P., Li, J., & Ying-zi, M. (2025) · Hepatobiliary & pancreatic diseases international · doi:10.1016/j.hbpd.2025.06.009 · Cited by 3
Fuchs, N. S., Kuncewicz, K., Gaamouch, F. E., & Gabr, M. T. (2025) · SLAS DISCOVERY · doi:10.1016/j.slasd.2025.100255 · Cited by 4
Anticancer Treatment Influences TREM2 in Tumor-Associated Macrophages in Lung Cancer
Cha, Y., Lee, E. H., Kim, C. Y., Choi, Y., Park, M. K., Lee, S.-H., Kim, E. Y., & Chang, Y. S. (2025) · Cancer research and treatment : official journal of Korean Cancer Association · doi:10.4143/crt.2024.1245 · Cited by 3
“Efferocytosis of apoptotic cell debris by macrophages is crucial in establishing an immune suppressive environment in the Tu by releasing anti-inflammatory or immunosuppressive signals, with TREM2 presumed to be central in this process [1,20].”
Li, B., Deng, S., Jiang, H., Zhu, W., Zhuo, B., Du, Y., & Meng, Z. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1323555 · Cited by 6
Kong, Y., Wang, D., Jin, X., Liu, Y., & Xu, H. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1334786 · Cited by 6
“Its ligands encompass various anionic molecules, freely present or bound to the cell membrane, including bacterial products, DNA, lipoproteins, and phospholipids (56).”
BackgroundThe flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids
(2025) · doi:10.7554/elife.102269.3 · Cited by 2
“4I ), affirming previous findings that TREM2 favors anionic ligands 32 .”
Metadata
- Authors
- Kober, D. L., & Brett, T. J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Brett, Tom J.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 429
- Issue
- 11
- Pages
- 1607-1629
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC5485854
- OpenAlex
- W2606080622
- Cited by
- 284
- References
- 161
- Citations by year
- 2026: 28 · 2025: 50 · 2024: 39 · 2023: 56 · 2022: 24 · 2021: 39 · 2020: 19 · 2019: 14 · 2018: 11 · 2017: 4
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P50AG005681)
- National Heart, Lung, and Blood Institute (R01HL119813)
- National Institute of General Medical Sciences (T32GM007067)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, myeloid cell activation, Alzheimer's disease, neurodegenerative diseases, chronic obstructive pulmonary disease, multiple sclerosis, stroke, receptor signaling, inflammatory diseases
- MeSH terms
- Animals, Disease Models, Animal, Health, Humans, Membrane Glycoproteins, Protein Binding, Receptors, Immunologic, Neurodegenerative Diseases
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