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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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Background
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Cited by
Sorted by citations
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Deczkowska, A., Weiner, A., & Amit, I. (2020) · Cell · doi:10.1016/j.cell.2020.05.003 · Cited by 648
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Jay, T. R., von Saucken, V. E., & Landreth, G. E. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0197-5 · Cited by 427
“Indeed, glycosaminoglycans and specifically heparin sulfate were found to modulate TREM2 binding [223] and it has been suggested that this may result in clustering of TREM2 on the membrane, thus potentially modulating TREM2 binding to other ligands [251].”
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Immune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336
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BackgroundInfluentialMicroglial TREM2/DAP12 signaling: a double-edged sword in neural diseases
Konishi, H., & Kiyama, H. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00206 · Cited by 300
The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
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“Some evidence suggests that sTREM2 binds to and sequesters TREM2 ligands, such as apolipoproteins, thus preventing these ligands from activating the TREM2 receptor (53, 54).”
Self-citationWang, X., He, Q., Zhou, C., Xu, Y., Liu, D., Fujiwara, N., Kubota, N., Click, A., Henderson, P., Vancil, J., et al. (2023) · Immunity · doi:10.1016/j.immuni.2022.11.013 · Cited by 262
Shao, F., Wang, X., Wu, H., Wu, Q., & Zhang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.825086 · Cited by 250
Andreone, B. J., Przybyla, L., Llapashtica, C., Rana, A., Davis, S. S., van Lengerich, B., Lin, K., Shi, J., Mei, Y., Astarita, G., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0650-6 · Cited by 233
Macrophage subsets in atherosclerosis as defined by single‐cell technologies
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“Macrophage TREM2 protects against infections, adipocyte hypertrophy, systemic hypercholesterolemia, body fat accumulation and glucose intolerance in mice [77,78] and has been shown to negatively correlate with human plaque stability [79].”
BackgroundZhong, L., Wang, Z., Wang, D., Wang, Z., Martens, Y. A., Wu, L., Xu, Y., Wang, K., Li, J., Huang, R., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0247-7 · Cited by 222
“A diverse set of potential TREM2 ligands that are anionic or lipidic in nature have been proposed [29].”
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Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152
“TREM2 can bind to an array of anionic ligands including phospholipids, lipoproteins, sulfatides, bacterial LPS and DNA, as well as various forms of amyloid-β, and it interacts with the transmembrane region of the adaptor protein DNAX-activation protein 12 (DAP12) to facilitate signal transduction [133] (Fig.”
BackgroundMicroglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
Nizami, S., Hall‐Roberts, H., Warrier, S., Cowley, S. A., & Di Daniel, E. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14618 · Cited by 147
“TREM2‐DAP12 activation regulates survival, proliferation, migration/chemotaxis, and phagocytosis (Kober & Brett, 2017; Takahashi, Rochford, & Neumann, 2005).”
BackgroundInfluentialHigh‐affinity interactions and signal transduction between Aβ oligomers and TREM2
Lessard, C. B., Malnik, S. L., Zhou, Y., Ladd, T. B., Cruz, P. E., Ran, Y., Chakrabaty, P., Mahan, T. E., Holtzman, D. M., Ulrich, J. D., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809027 · Cited by 156
“TREM2 appears to be a promiscuous receptor and has been shown to interact with cellular debris, bacteria, anionic phospholipids, nucleic acids, and apolipoprotein E (APOE; Atagi et al, 2015; Bailey et al, 2015; Yeh et al, 2016; Kober & Brett, 2017; Song et al, 2017).”
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Aldana, B. I. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.03.006 · Cited by 158
“Recently, the triggering receptor expressed on myeloid cells-2 (TREM-2) expressed in microglia has received attention in the field of neurodegeneration as coding variants that increase the risk of AD and other neurodegenerative diseases have been identified [109,110].”
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“The ligands of TREM2 include bacterial products, DNA, lipoproteins, and phospholipids [24].”
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“In recent years, several studies have distinguished a distinct subpopulation of macrophages that express high levels of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) [5 – 7].”
Molecular and metabolic heterogeneity of astrocytes and microglia
Hasel, P., Aisenberg, W. H., Bennett, F. C., & Liddelow, S. A. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.03.006 · Cited by 135
TREM2 ectodomain and its soluble form in Alzheimer’s disease
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“Functions of TREM2 ectodomain and its soluble form in AD pathology The shedding of the TREM2 ectodomain, which is triggered by different ligands, is a fundamental process during TREM2-induced cell signaling [32].”
BackgroundDistinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
Yao, H., Coppola, K., Schweig, J. E., Crawford, F., Mullan, M., & Paris, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00457 · Cited by 110
“It remains also possible that different TREM2 ligands may have different activities toward TREM2 signaling as previously postulated (Turnbull et al., 2006; Kober and Brett, 2017).”
BackgroundRoles of Macrophages in Atherogenesis
Farahi, L., Sinha, S. K., & Lusis, A. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.785220 · Cited by 117
Understanding, predicting and achieving liver transplant tolerance: from bench to bedside
Thomson, A. W., Vionnet, J., & Fueyo, A. S. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0334-4 · Cited by 107
Desale, S. E., Chidambaram, H., & Chinnathambi, S. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00036-1 · Cited by 99
Wijeyekoon, R., Kronenberg‐Versteeg, D., Scott, K. M., Hayat, S., Kuan, W., Evans, J., Breen, D. P., Cummins, G. A., Jones, J., Clatworthy, M. R., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.01.018 · Cited by 105
TREM2 in Alzheimer’s Disease: Microglial Survival and Energy Metabolism
Zheng, H., Cheng, B., Li, Y., Li, X., Chen, X., & Zhang, Y.-W. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00395 · Cited by 94
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
de Oliveira, J., Kucharska, E., Garcez, M. L., Rodrigues, M. S., Quevedo, J., Moreno‐González, I., & Budni, J. (2021) · Cells · doi:10.3390/cells10102581 · Cited by 110
“TREM2 ligands include bacteria, bacterial cell components such as lipopolysaccharide (LPS), lipoproteins, such as apolipoprotein A (ApoA), ApoB, ApoE, low-density lipoprotein (LDL), DNA, HSP60 chaperone protein, and Aβ [109].”
Distinct roles of TREM2 in central nervous system cancers and peripheral cancers
Zhong, J., Xing, X., Gao, Y., Pei, L., Lu, C., Sun, H., Lai, Y., Du, K., Xiao, F., Yang, Y., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.05.001 · Cited by 100
TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis
Guo, X. Q., Li, B., Wen, C., Zhang, F. S., Xiang, X., Nie, L., Chen, J., & Mao, L. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04786-9 · Cited by 100
“TREM2 is a transmembrane receptor belonging to the immunoglobulin family with a wide range of ligands, including lipids, lipoproteins, cellular debris, and DNA [11].”
BackgroundFunctional insights from biophysical study of TREM2 interactions with apoE and Aβ 1‐42
Kober, D. L., Stuchell‐Brereton, M. D., Kluender, C. E., Dean, H. B., Strickland, M. R., Steinberg, D. F., Nelson, S. S., Baban, B. A., Holtzman, D. M., Frieden, C., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12194 · Cited by 86
“1-299); (2) C-term deletion (1-238); (3) C-term and partial hinge deletion (1-191); or (4) C-term and complete hinge deletion (1-169) (Figure 4.”
Self-citationBrain Injury–Mediated Neuroinflammatory Response and Alzheimer’s Disease
Kempuraj, D., Ahmed, M. E., Selvakumar, G. P., Thangavel, R., Dhaliwal, A. S., Dubova, I., Mentor, S., Premkumar, K., Saeed, D., Zahoor, H., et al. (2019) · The Neuroscientist · doi:10.1177/1073858419848293 · Cited by 90
TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
Labiano, I., Agirre-Lizaso, A., Olaizola, P., Echebarria, A., Huici-Izagirre, M., Olaizola, I., Esparza-Baquer, A., Sharif, O., Hijona, E., Milkiewicz, P., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.05.044 · Cited by 78
Tagliatti, E., Desiato, G., Mancinelli, S., Bizzotto, M., Gagliani, M. C., Faggiani, E., Hernández‐Soto, R., Cugurra, A., Poliseno, P., Miotto, M., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.12.002 · Cited by 90
“Next, we investigated changes in gene expression among cells exhibiting different densities across the specific pseudo-time value interval (17–22, gray) and identified, among the significantly deregulated genes between conditions, key mitochondrial genes: structural regulators of the outer…”
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“Furthermore, TREM2 signaling is critical for myeloid cell survival and proliferation in the AD brain, and reduces plaque-associated neurotoxicity by regulating compaction of toxic Aβ deposits (35,42) .”
BackgroundInteractions between glial cells and the blood-brain barrier and their role in Alzheimer's disease
Zhao, M., Jiang, X., Zhang, H., Sun, J., Pei, H., Ma, L., Cao, Y., & Li, H. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101483 · Cited by 86
Coelho, I., Duarte, N., Barros, A., Macedo, M. P., & Penha-Gonçalves, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.616044 · Cited by 70
“Triggering receptor expressed on myeloid cells-2 (Trem-2) is a transmembrane immune receptor typically expressed in the monocyte/macrophage lineage (11).”
BackgroundTREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies
Zhang, L., Xiang, X., Li, Y., Bu, G., & Chen, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00834-z · Cited by 87
“Binding of ligands—including lipids, lipoproteins, apolipoproteins, or Aβ—to TREM2 triggers intracellular signaling cascades that regulate microglial responses to AD pathology [10, 12].”
Wang, Y., Cao, C., Zhu, Y., Fan, H., Liu, Q., Liu, Y., Chen, K., Wu, Y., Liang, S., Li, M., et al. (2022) · Cell Death & Disease · doi:10.1038/s41419-022-05193-x · Cited by 69
“It was reported that TREM2 can bind to bacterial anionic molecules, such as lipopolysaccharide (LPS), dextran sulfates and cell debris, while its downstream signals vary in response to distinct stimulation[15].”
BackgroundLiu, C., Li, P., Li, H., Wang, S., Ding, L., Wang, H., Ye, H., Jin, Y., Hou, J., Fang, X., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2050-9 · Cited by 72
Magno, L., Bunney, T. D., Mead, E., Svensson, F., & Bictash, M. N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00436-5 · Cited by 64
The markers to delineate different phenotypes of macrophages related to metabolic disorders
Wei, Q., Deng, Y., Yang, Q., Zhan, A., & Wang, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1084636 · Cited by 66
“4 TREM2 TREM2 is a lipid-sensing extracellular receptor expressed by the myeloid lineage (64, 65).”
BackgroundHall-Roberts, H., Agarwal, D., Obst, J., Smith, T. B., Monzón-Sandoval, J., Di Daniel, E., Webber, C., James, W. S., Mead, E., Davis, J. B., et al. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00709-z · Cited by 62
“Secretion is SYK-dependent, and TREM2 KO pMac express reduced levels of TGFβ1.”
BackgroundInfluentialSun, Y., Wei, K., Liao, X., Wang, J., Gao, L., & Pang, B. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5580 · Cited by 63
“The TREM2 R47H variant loses cE recognition capacity, causing lipid droplet dysmetabolism and impaired remyelination (15,76,137,138).”
Cao, Y., Zhao, L.-W., Chen, Z.-X., & Li, S.-H. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1430465 · Cited by 65
Chernick, D., Ortiz‐Valle, S., Jeong, A., Qu, W., & Li, L. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134306 · Cited by 64
Troutman, T. D., Kofman, E. R., & Glass, C. K. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.004 · Cited by 62
Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice
Qu, W., & Li, L. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2193-20.2020 · Cited by 71
“Various putative ligands for TREM2, including lipids, apolipoproteins, and amyloid-b (Ab ) have been identified (Kober and Brett, 2017).”
BackgroundGervois, P., & Lambrichts, I. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01668 · Cited by 59
“However, the identification of the entire spectrum of endogenous TREM2 ligands and clarification of the ligandspecific physiological TREM2-mediated response in health and disease remains challenging [reviewed by Kober and Brett (56)].”
BackgroundLiu, C., Chyr, J., Zhao, W., Xu, Y., Ji, Z., Tan, H., Soto, C. A., Zhou, X., & Initiative, A. D. N. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00410 · Cited by 51
“For microglia are the brain-resident immune cells and TREM2 gene plays a crucial role in microglia function (Keren-Shaul et al., 2017; Kober and Brett, 2017), we will study how they affect the progression of AD for further research.”
BackgroundThe role of TREM2 in Alzheimer’s disease: from the perspective of Tau
Huang, W., Huang, J., Huang, N., & Luo, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1280257 · Cited by 49
Dual role of microglia in neuroinflammation and neurodegenerative diseases
Ajoolabady, A., Kim, B., Abdulkhaliq, A. A., Ren, J. T., Bahijri, S., Tuomilehto, J. O., Borai, A., Khan, J., & Praticò, D. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107133 · Cited by 62
Tran, K. M., Kawauchi, S., Kramár, E. A., Rezaie, N., Liang, H. Y., Sakr, J., Gómez-Arboledas, Á., Arreola, M. A., da Cunha, C., Phan, J., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00598-4 · Cited by 55
“TREM2 can bind many polyanionic ligands including bacterial lipopolysaccharide, lipoproteins and phospholipids whose presence are often associated with infection or cellular damage [5].”
Düsedau, H. P., Steffen, J., Figueiredo, C. A., Boehme, J. D., Schultz, K., Erck, C., Körte, M., Faber‐Zuschratter, H., Smalla, K., Dieterich, D. C., et al. (2021) · mBio · doi:10.1128/mbio.01776-21 · Cited by 71
“In contrast, mRNA levels of Trem2, an innate immune receptor implicated in cell activation and phagocytosis (43), and the inducible nitric oxide synthase (Nos2) remained unaffected upon IAV infection (Fig.”
BackgroundDeming, Y. K., Li, Z., Benítez, B. A., & Cruchaga, C. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1486823 · Cited by 51
“Other studies have reported other ligands such as heat shock protein 60 (HSP60) and apolipoproteins [70].”
BackgroundBarschke, P., Oeckl, P., Steinacker, P., Al Shweiki, M. R., Weishaupt, J. H., Landwehrmeyer, G. B., Anderl-Straub, S., Weydt, P., Diehl-Schmid, J., Danek, A., et al. (2020) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-322476 · Cited by 45
Neurodegeneration cell per cell
Balusu, S., Praschberger, R., Lauwers, E., Strooper, B. D., & Verstreken, P. (2023) · Neuron · doi:10.1016/j.neuron.2023.01.016 · Cited by 53
“TREM2 binds to various ligands, including Aβ oligomers (reviewed in 51 ).”
Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology
Wood, J. I., Wong, E., Joghee, R., Balbaa, A., Vitanova, K. S., Stringer, K. M., VanSchoiack, A., Phelan, S.-L. J., Launchbury, F., Desai, S., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111686 · Cited by 65
“A possible candidate would be a phospholipid, such as phosphotidylserine that has been suggested to be an ‘‘eat me’’ signal on damaged synapses.(46,47) This is consistent with a role for microglia in removing Ab-induced dystrophic synapses to limit the spread of damage along axons or dendrites.”
BackgroundZhang, L., Xu, J., Gao, J., Wu, Y., Yin, M., & Zhao, W. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0084 · Cited by 51
TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain
Fruhwürth, S., Reinert, L. S., Öberg, C., Sakr, M., Henricsson, M., Zetterberg, H., & Paludan, S. R. (2023) · Science Advances · doi:10.1126/sciadv.adf5808 · Cited by 46
“DNA, different lipids, and complex carbohydrates, which are present on viral particles and stressed cells, have been reported as TREM2 agonists (19), and further studies are needed to uncover the HSV1-microglia interactions in more detail.”
BackgroundXu, H., Mu, S., & Qin, W. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.08.130 · Cited by 42
The therapeutic potential of TREM2 in cancer
Wolf, E. M., Fingleton, B., & Hasty, A. H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.984193 · Cited by 51
“While the strength and direction of TREM2 downstream signaling is differentially modulated upon interaction with various ligands, many aspects of TREM2 interaction and the downstream signals propagated remain to be fully understood (7).”
BackgroundInfluentialAfrican Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants
Schindler, S. E., Cruchaga, C., Joseph, A., McCue, L. M., Farias, F., Wilkins, C. H., Deming, Y. K., Henson, R. L., Mikesell, R. J., Piccio, L. M., et al. (2021) · Neurology Genetics · doi:10.1212/nxg.0000000000000571 · Cited by 50
Dean, H. B., Roberson, E. D., & Song, Y. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01252 · Cited by 43
“Initial reports suggested that surface variants may cause neurodegenerative disease by disrupting the electrostatics of this PLIR—which includes residues of CDR2 and the βC” strand— thereby impairing binding of a subset of polyanionic lipids (40, 42, 54).”
BackgroundAlzheimer’s disease pathological lesions activate the spleen tyrosine kinase
Schweig, J. E., Yao, H., Beaulieu‐Abdelahad, D., Ait‐Ghezala, G., Mouzon, B., Crawford, F., MULLAN, M. J., & Paris, D. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0472-2 · Cited by 40
“flammation and synaptic loss in AD mouse models [17].”
Irfan, M., Evonuk, K. S., & DeSilva, T. M. (2022) · The FEBS Journal · doi:10.1111/febs.16190 · Cited by 39
Wang, Q., Wu, Y., Jiang, G., & Huang, X. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03124-6 · Cited by 36
“The TREM2 receptor interacts with a variety of ligands, primarily anionic molecules, including bacterial products, DNA, and lipoproteins [17].”
Reactive oxygen species trigger inflammasome activation after intracellular microbial interaction
Rosa, C. P., Belo, T. C. A., Santos, N. C. D. M., Silva, E. N., Gasparotto, J., Corsetti, P. P., & de Almeida, L. A. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122076 · Cited by 40
Bennett, J. P., Keeney, P. M., & Brohawn, D. G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00235 · Cited by 38
The influence of inflammation and frailty in the aging continuum
Arosio, B., Ferri, E., Mari, D., Tobaldini, E., Vitale, G., & Montano, N. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111872 · Cited by 42
Smart, C. D., Fehrenbach, D. J., Wassenaar, J. W., Agrawal, V., Fortune, N. L., Dixon, D., Cottam, M. A., Hasty, A. H., Hemnes, A. R., Doran, A. C., et al. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad093 · Cited by 55
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 48
“(4) The ITIM of CD33 combines with SHP, which inhibits the phosphorylation of SYK and the downstream signaling pathways.”
BackgroundInfluentialObst, J., Hall-Roberts, H. L., Smith, T. B., Kreuzer, M., Magno, L., Di Daniel, E., Davis, J. B., & Mead, E. (2021) · Scientific Reports · doi:10.1038/s41598-021-96144-7 · Cited by 36
Role of TREM2 in Alzheimer’s Disease: A Long Road Ahead
Kulkarni, B., Kumar, D., Martins, N. A., & Sellamuthu, S. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02477-9 · Cited by 53
“The major ligands of TREM2 are yet to be identified and there is also a possibility that TREM2 is an unselective receptor [77].”
BackgroundSingh, H., Rai, V., Nooti, S. K., & Agrawal, D. K. (2021) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1883587 · Cited by 47
Microglial Drug Targets in AD: Opportunities and Challenges in Drug Discovery and Development
Biber, K., Bhattacharya, A., Campbell, B. M., Piro, J. R., Rohe, M., Staal, R. G. W., Talanian, R. V., & Möller, T. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00840 · Cited by 39
Gupta, C., Xu, J., Jin, T., Khullar, S., Liu, X., Alatkar, S., Cheng, F., & Wang, D. (2022) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1010287 · Cited by 33
“Triggering receptor expressed on myeloid cells 2 (TREM2) is a type I transmembrane protein expressed on the surface of microglia, binds to phospholipids [53] and is hypothesized to be triggering the phagocytosis of Aβ plaques [54].”
BackgroundCarrier, M., Šimončičová, E., St‐Pierre, M., McKee, C., & Tremblay, M. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.749737 · Cited by 37
TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy
Qiu, H., Shao, Z., Wen, X., Jiang, J., Ma, Q., Wang, Y., Huang, L., Ding, X., & Zhang, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.716710 · Cited by 32
Movers and shakers: Microglial dynamics and modulation of neural networks
Whitelaw, B. S., Stoessel, M. B., & Majewska, A. K. (2022) · Glia · doi:10.1002/glia.24323 · Cited by 34
“TREM2 binds a large variety of anionic ligands, including microbial products, DNA, and phospholipids like PS (Kober & Brett, 2017).”
BackgroundTargeting TREM2 for Parkinson’s Disease: Where to Go?
Li, X., & Zhang, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.795036 · Cited by 38
“org 2 cytosolic tail region, whose single transmembrane helix interacts with DAP12 to mediate downstream signaling, short cytosolic tail terminates signals that lack signal transduction or trafficking motifs (27).”
BackgroundMicroglia Process α‐Synuclein Fibrils and Enhance their Pathogenicity in a TREM2‐Dependent Manner
Xiong, M., Xia, D., Yu, H., Meng, L., Zhang, X., Chen, J., Tian, Y., Yuan, X., Niu, X., Nie, S., et al. (2024) · Advanced Science · doi:10.1002/advs.202413451 · Cited by 21
Yu, F., Yu, N., Peng, J., Zhao, Y., Zhang, L., Wang, X., Xu, X., Zhou, J., & Wang, F. (2021) · The FASEB Journal · doi:10.1096/fj.202100157rr · Cited by 36
Ferrara, S. J., Chaudhary, P., DeBell, M. J., Marracci, G., Miller, H., Calkins, E., Pocius, E., Napier, B., Emery, B., Bourdette, D., et al. (2021) · bioRxiv · doi:10.1101/2021.01.25.428149 · Cited by 31
“The general consensus is that TREM2 does not bind to a single, discrete ligand, but instead binds and is activated by various proteins, lipids, and other debris arising from damaged cells.(10) Here we report the discovery that Trem2 is a positively regulated thyroid hormone target”
BackgroundInduced pluripotent stem cell-derived macrophages as a platform for modelling human disease
Tiwari, S. K., Wong, W. J., Moreira, M., Pasqualini, C., & Ginhoux, F. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01081-x · Cited by 36
“TREM2 can bind various ligands to regulate microglial cell functions including proliferation, survival, chemotaxis, phagocytosis, activation and metabolism 79,80 .”
Greven, J. A., Wydra, J. R., Greer, R. A., Zhi, C., Price, D. A., Svoboda, J. D., Camitta, C. L. M., Washington, M., Leung, D. W., Song, Y., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00795-9 · Cited by 42
“Residues highlighted in grey were not screened. were few known ligands for TREM2, outside of DNA and bacterial cell membrane debris [34].”
Self-citationThe diverse roles of macrophages in metabolic inflammation and its resolution
Ray, A. G., Odum, O., Wiseman, D., & Weinstock, A. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1147434 · Cited by 31
“It was further found that the levels of C16:0 ceramides are decreased in VLDLR deficient macrophages, which are less inflammatory, through the reduced activity of mitogen-activated protein kinases (MAPK) (Kober and Brett, 2017).”
BackgroundTREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology
Yu, C.-J., Wang, M., Ruiyang, L., Wei, T., Yang, H.-C., Yin, Y., Mi, Y., Qin, Q., & Tang, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03100-1 · Cited by 34
“TREM2, which belongs to the TREM family, can bind to various ligands, such as Aβ and APOE, and transmit signals via DAP12/DAP10 [13, 88, 89, 91, 105].”
BackgroundMicroglial TREM2 at the Intersection of Brain Aging and Alzheimer’s Disease
Qu, W., & Li, L. (2021) · The Neuroscientist · doi:10.1177/10738584211040786 · Cited by 38
“In addition to binding secreted molecules, TREM2 can also bind to astrocytes, neurons, and apoptotic cells, creating a cell-cell interaction and signaling between microglia and other cell types (Kober and Brett 2017).”
BackgroundTREM2, microglial and ischemic stroke
Wang, H., Li, X., Wang, Q., Ma, J., Gao, X., & Wang, M. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578108 · Cited by 32
Korvatska, O., Kiianitsa, K., Ratushny, A. V., Matsushita, M. M., Beeman, N. E., Chien, W., Satoh, J., Dorschner, M. O., Keene, C. D., Bammler, T. K., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.559342 · Cited by 31
“Whereas pathogenic missense PLOSL variants affect protein folding and stability, decreasing TREM2 surface localization, R47H, and other AD-associated mutations alter the ligand-binding interface of TREM2 (54, 55).”
BackgroundMcKee, C., Hoffos, M., Vecchiarelli, H. A., & Tremblay, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1125982 · Cited by 38
“The binding of TREM2 ligands including Aβ, apolipoproteins, phospholipids, and lipopolysaccharides (Kober and Brett, 2017) activates DNAX-activating protein of 12 kDa (DAP12), TREM2’s binding partner, increasing microglial migration, lipid metabolism, autophagy, and phagocytosis, notably of myelin (Mazaheri et al.”
BackgroundAutophagy & Phagocytosis in Neurological Disorders and their Possible Cross-talk
Li, G., Sherchan, P., Tang, Z., & Tang, J. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210407150632 · Cited by 29
“TREM2-DAP12 complex induces the activation of the spleen tyrosine kinase (Syk)/ phospholipase C-gamma (PLC-γ)/phosphoinositide 3-kinase (PI3K) signaling pathway, leading to the promotion of microglia phagocytosis [59].”
BackgroundRhein-attenuates LPS-induced acute lung injury via targeting NFATc1/Trem2 axis
Li, X., Xiao, C., Yuan, J., Chen, X., Li, Q., & Shen, F. (2023) · Inflammation Research · doi:10.1007/s00011-023-01746-8 · Cited by 27
“Through the interactions with different co-receptors and ligands, it can even attain the opposite downstream signal effect [54].”
BackgroundInhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis
Sigalov, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168857 · Cited by 26
“Similarly to TREM-1, numerous molecules were proposed as potential ligand(s) for TREM-2, ranging from various anionic molecules, such as phospholipids and proteoglycans, to apolipoproteins (apos) and heat shock proteins [45].”
BackgroundDesimone, A. M. L., Hong, J., Brockie, S. T., Yu, W., Laliberté, A. M., & Fehlings, M. G. (2021) · JCI Insight · doi:10.1172/jci.insight.149227 · Cited by 29
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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