Cited by 284Neuroinflammation and Neurodegeneration MechanismsInflammation biomarkers and pathwaysPhagocytosis and Immune Regulation

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TREM2-Ligand Interactions in Health and Disease

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Kober, Daniel L., Brett, Tom J.·2017·Journal of Molecular Biology

DOI 10.1016/j.jmb.2017.04.004PMC PMC5485854

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Abstract

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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Background
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Background
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Background
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BackgroundResultInfluential
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Background
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Background
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Background
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Background
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BackgroundInfluential
TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
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Coding variants in TREM2 increase risk for Alzheimer's disease
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“In addition to the membrane-bound form, soluble TREM2 ectodomains (sTREM2) can be generated by proteolytic processing that occurs within the protein stalk [2] or by alternative splicing [3] (Fig 1B).”
Background
Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation
Piccio, L. M., Buonsanti, C., Cella, M., Tassi, I., Schmidt, R. E., Fenoglio, C., Rinker, J. R., Naismith, R. T., Panina‐Bordignon, P., Passini, N., et al. (2008) · Brain · doi:10.1093/brain/awn217 · Cited by 311 · cited 1×
“Soluble TREM2 was first identified in the CSF of MS patients and neuroinflammatory patients [69], and has since been identified in a number of AD cohorts [52–54, 70].”
Background
The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
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Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease
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Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
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Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
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Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage
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TREM2 regulates microglial cell activation in response to demyelination in vivo
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“Instead, Trem2 deficiency was associated with decreased expression of lipid metabolism enzymes and a failure to degrade myelin debris [64, 65].”
Background
Pattern Recognition by TREM-2: Binding of Anionic Ligands
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You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling
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Background
Efficient colonic mucosal wound repair requires Trem2 signaling
Seno, H., Miyoshi, H., Brown, S. L., Geske, M. J., Colonna, M., & Stappenbeck, T. S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803343106 · Cited by 286 · cited 2×
“In the biopsy injury model, the first step in healing was for epithelial cells to form a layer over the wound, which the authors hypothesized would reduce exposure to bacteria and therefore reduce strong TLR signals that are known to down-regulate TREM2 [72].”
Background
Blockade of TREM‐2 exacerbates experimental autoimmune encephalomyelitis
Piccio, L., Buonsanti, C., Mariani, M., Cella, M., Gilfillan, S., Cross, A. H., Colonna, M., & Panina‐Bordignon, P. (2007) · European Journal of Immunology · doi:10.1002/eji.200636837 · Cited by 284
Activating and inhibitory functions of DAP12
Turnbull, I. R., & Colonna, M. (2007) · Nature Reviews Immunology · doi:10.1038/nri2014 · Cited by 273
Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury
Suárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · cited 3×
“While these possibilities are explored, CSF sTREM2 certainly has potential as a biomarker for microgliosis during AD onset [48]”
BackgroundInfluential
Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis
Takegahara, N., Takamatsu, H., Toyofuku, T., Tsujimura, T., Okuno, T., Yukawa, K., Mizui, M., Yamamoto, M., Prasad, D. V., Suzuki, K., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1416 · Cited by 270
DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming.
Bakker, A. B., Hoek, R., Cerwenka, A., Blom, B., Lucian, L., McNeil, T., Murray, R., Phillips, L., Sedgwick, J., & Lanier, L. (2000) · Immunity · doi:10.1016/s1074-7613(00)00034-0 · Cited by 269
TREM2 Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6237 · Cited by 262 · cited 2×
“Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16].”
Background
Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Cella, M., Buonsanti, C., Strader, C., Kondo, T., Salmaggi, A., & Colonna, M. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20022220 · Cited by 256 · cited 9×
“Indeed, TREM2 can bind primary macrophages [98] and DCs [100].”
BackgroundInfluential
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2
Klünemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000160304.00003.ca · Cited by 254
Structural basis of semaphorin–plexin signalling
Janssen, B. J. C., Robinson, R. A., Pérez‐Brangulí, F., Bell, C., Mitchell, K. J., Siebold, C., & Jones, E. Y. (2010) · Nature · doi:10.1038/nature09468 · Cited by 250
TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice
Frank, S., Burbach, G. J., Bonin, M., Walter, M., Streit, W., Bechmann, I., & Deller, T. (2008) · Glia · doi:10.1002/glia.20710 · Cited by 247 · cited 1×
“Within human AD brain, laser microdissection showed Trem2 is highly expressed on plaque-associated microglia [44], and high resolution microscopy techniques showed that TREM2 protein is concentrated on microglia processes that are in contact with amyloid beta (Aβ) plaques [45].”
Background
TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria
N’Diaye, E.-N., Branda, C., Branda, S. S., Nevarez, L., Colonna, M., Lowell, C. A., Hamerman, J. A., & Seaman, W. E. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200808080 · Cited by 243
Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Kober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238
Self-citation
Abstract 9: Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) deficiency Attenuates Phagocytic Activities of Microglia and Exacerbates Ischemic Damage in Experimental Stroke
Kawabori, M., Kacimi, R., Kauppinen, T. M., Calosing, C., Kim, J. Y., Christine, C., Nakamura, M. C., & Yenari, M. (2014) · Stroke · doi:10.1161/str.45.suppl_1.9 · Cited by 226 · cited 4×
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
BackgroundResultInfluential
Immunological functions of the neuropilins and plexins as receptors for semaphorins
Kumanogoh, A., & Kikutani, H. (2013) · Nature reviews. Immunology · doi:10.1038/nri3545 · Cited by 221
TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.016 · Cited by 219 · cited 5×
“TREM2 inhibits inflammatory cytokine production in cultured microglia following exposure to apoptotic neurons [142], and Trem2-deficient and haploinsufficient microglia have impaired microgliosis and don’t properly respond to plaques [30, 42, 45, 47, 143] (Fig.”
BackgroundResultInfluential
The immunology of neurodegeneration
Czirr, E., & Wyss‐Coray, T. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58656 · Cited by 218 · cited 1×
“Therefore, preventing or containing disease will require a more sophisticated understanding of the protective and pathogenic features of the inflammatory process [57].”
Background
TREM-1 ligand expression on platelets enhances neutrophil activation
Haselmayer, P., Große‐Hovest, L., von Landenberg, P., Schild, H., & Radsak, M. P. (2007) · Blood · doi:10.1182/blood-2007-01-069195 · Cited by 211
DAP12-mediated Signal Transduction in Natural Killer Cells
McVicar, D. W., Taylor, L. S., Gosselin, P., Willette‐Brown, J., Mikhael, A., Geahlen, R. L., Nakamura, M. C., Linnemeyer, P. A., Seaman, W. E., Anderson, S. K., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32934 · Cited by 210
Metalloproteinases Shed TREM-1 Ectodomain from Lipopolysaccharide-Stimulated Human Monocytes1
Gómez-Piña, V., Soares-Schanoski, A., Rodríguez-Rojas, A., del Fresno, C., García, F., Vallejo-Cremades, M. T., Fernández-Ruíz, I., Arnalich, F., Fuentes-Prior, P., & López-Collazo, E. (2007) · Journal of Immunology · doi:10.4049/jimmunol.179.6.4065 · Cited by 208
TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
Wu, K., Byers, D. E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A. C., Cella, M., Gilfilan, S., Colonna, M., Kober, D. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141732 · Cited by 207 · cited 3×
“In the first study of sTREM2 function, application of sTREM2 (residues 19–136) to cultured BMDMs resulted in ERK and MAPK14 activation that persisted several hours and prevented apoptosis following M-CSF withdrawal [71].”
BackgroundSelf-citation
CNS manifestations of Nasu–Hakola disease
Bm, J., Autti, T., Raininko, R., Partanen, J., Salonen, O., Puranen, M., Hakola, P., & Haltia, M. (2001) · Neurology · doi:10.1212/wnl.56.11.1552 · Cited by 205
The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205 · cited 1×
“Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16].”
Background
Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells
Simhadri, V. R., Andersen, J. F., Calvo, E., Choi, S., Coligan, J. E., & Borrego, F. (2012) · Blood · doi:10.1182/blood-2011-08-372425 · Cited by 196
Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis
Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 190
The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system
Rao, N. L., Dodge, I., & Band, H. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.5.753 · Cited by 190 · cited 1×
“Furthermore, as noted above, the E3 ubiquitin ligase Cbl is recruited to LAB and forms a complex with LAB and PI3K [92] to target Src and Syk for ubiquitination and degradation [94].”
Background
Gene Structure, Expression Pattern, and Biological Activity of Mouse Killer Cell Activating Receptor-associated Protein (KARAP)/DAP-12*
Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Bléry, M., Moqrich, A., Gautheret, D., Djabali, M., Mattéi, M., & Vivier, É. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.34115 · Cited by 186 · cited 1×
“DAP12 forms a disulfide-bonded homodimer with two intermolecular disulfide bonds contained within in a short ectodomain (14 residues in human aa 28–41 [79], 16 in mouse aa 28–43 [80]).”
Background
Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia
Cuyvers, E., Bettens, K., Philtjens, S., Langenhove, T. V., Gijselinck, I., van der Zee, J., Engelborghs, S., Vandenbulcke, M., Dongen, J. V., Geerts, N., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.009 · Cited by 185 · cited 1×
“Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16].”
Background
TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance
Xiang, X., Werner, G., Bohrmann, B., Liesz, A., Mazaheri, F., Capell, A., Feederle, R., Knuesel, I., Kleinberger, G., & Haass, C. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606370 · Cited by 183
The structural basis for intramembrane assembly of an activating immunoreceptor complex
Call, M. E., Wucherpfennig, K. W., & Chou, J. J. (2010) · Nature Immunology · doi:10.1038/ni.1943 · Cited by 181
Insights into TREM2 biology by network analysis of human brain gene expression data
Forabosco, P., Ramasamy, A., Trabzuni, D., Walker, R., Smith, C., Bras, J., Levine, A. P., Hardy, J., Pocock, J. M., Guerreiro, R., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.05.001 · Cited by 180 · cited 1×
“Within the normal human brain, TREM2 is expressed most highly in white matter, with transcripts detected in all major areas [34].”
Background
TREM2 and β-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis
Otero, K., Shinohara, M., Zhao, H., Cella, M., Gilfillan, S., Colucci, A., Faccio, R., Ross, F. P., Teitelbaum, S. L., Takayanagi, H., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102836 · Cited by 177
TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice
Jiang, T., Zhang, Y.-D., Chen, Q., Gao, Q., Zhu, X.-C., Zhou, J.-S., Shi, J.-Q., Lu, H., Tan, L., & Yu, J.-T. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.01.028 · Cited by 176 · cited 1×
“While no studies using Trem2−/− mice have been published in tau models, Jiang and colleagues have conducted studies altering TREM2 expression in vivo by lentiviral overexpression (under a Cd11b promoter) or shRNA knockdown [50, 51] in the P301S tau transgenic model.”
Background
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.
Klünemann, H., Ridha, B., Magy, L., Wherrett, J., Hemelsoet, D., Keen, R., Bleecker, J. D., Rossor, M., Marienhagen, J., Klein, H., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000216105.11788.0f · Cited by 174
TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells
Ito, H., & Hamerman, J. A. (2012) · European Journal of Immunology · doi:10.1002/eji.201141679 · Cited by 173 · cited 8×
“Indeed, TREM2 can bind primary macrophages [98] and DCs [100].”
BackgroundInfluential
Heterozygous TREM2 mutations in frontotemporal dementia
Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.017 · Cited by 173 · cited 1×
“Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16].”
Background
Specific lipid recognition is a general feature of CD300 and TREM molecules
Cannon, J. P., O’Driscoll, M., & Litman, G. W. (2011) · Immunogenetics · doi:10.1007/s00251-011-0562-4 · Cited by 165
Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia
Sessa, G., Podini, P., Mariani, M., Meroni, A., Spreafico, R., Sinigaglia, F., Colonna, M., Panina, P., & Meldolesi, J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03729.x · Cited by 165 · cited 10×
“Although there have been reports of TREM2 detection on non-myeloid/microglial cells in the CNS [4, 36], these cases have largely used immunostaining methods to identify neuronal expression of TREM2, which may identify sTREM2 produced by microglia that is released and bound to neurons which express a TREM2 ligand [26,…”
BackgroundInfluential
TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function
Humphrey, M. B., Daws, M. R., Spusta, S. C., Niemi, E. C., Torchia, J. A., Lanier, L. L., Seaman, W. E., & Nakamura, M. C. (2006) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.051016 · Cited by 162
Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · cited 1×
“Indeed, TLRs and many other inflammatory receptors are stimulated directly by Aβ, causing the production of inflammatory cytokines which create a cytotoxic, inflammatory environment [63].”
Background
A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158
TREM2 Function in Alzheimer’s Disease and Neurodegeneration
Ulrich, J. D., & Holtzman, D. M. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00313 · Cited by 154
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153
The surface‐exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor
Stefano, L., Racchetti, G., Bianco, F., Passini, N., Gupta, R. S., Panina‐Bordignon, P., & Meldolesi, J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06130.x · Cited by 150
Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease
Giraldo, M., Lopera, F., Siniard, A. L., Corneveaux, J. J., Schrauwen, I., Carvajal, J., Muñoz, C., Ramirez-Restrepo, M., Gaiteri, C., Myers, A. J., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.02.016 · Cited by 147
Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease
Henjum, K., Almdahl, I. S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., & Nilsson, L. N. G. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0182-1 · Cited by 145
Inhibition of Immune Responses by ITAM-Bearing Receptors
Hamerman, J. A., & Lanier, L. L. (2006) · Science s STKE · doi:10.1126/stke.3202006re1 · Cited by 143
DAP12 Couples c-Fms Activation to the Osteoclast Cytoskeleton by Recruitment of Syk
Zou, W., Reeve, J., Liu, Y.-L., Teitelbaum, S. L., & Ross, F. P. (2008) · Molecules and Cells · doi:10.1016/j.molcel.2008.06.023 · Cited by 143
DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response
Zhong, L., Chen, X.-F., Zhang, Z.-L., Wang, Z., Shi, X.-Z., Xu, K., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.645986 · Cited by 133
Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke
Sieber, M. W., Jaenisch, N., Brehm, M., Guenther, M., Linnartz‐Gerlach, B., Neumann, H., Witte, O. W., & Frahm, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0052982 · Cited by 128 · cited 2×
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
BackgroundResult
Mutations inTREM2lead to pure early-onset dementia without bone cysts
Chouery, É., Delague, V., Bergougnoux, A., Koussa, S., Serre, J., & Mégarbané, A. (2008) · Human Mutation · doi:10.1002/humu.20836 · Cited by 121 · cited 1×
“The TREM2 variants include splice site [7, 9] early stop sites [7, 10–12], and coding ectodomain mutations [7, 8, 13–15].”
Background
Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease
Gispert, J. D., Suárez‐Calvet, M., Monté, G. C., Tucholka, A., Falcón, C., Rojas, S., Rami, L., Sánchez‐Valle, R., Lladó, A., Kleinberger, G., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.005 · Cited by 116
Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice
Jiang, T., Tan, L., Zhu, X.-C., Zhou, J.-S., Cao, L., Tan, M.-S., Wang, H.-F., Chen, Q., Zhang, Y.-D., & Yu, J.-T. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.08.019 · Cited by 111 · cited 1×
“While no studies using Trem2−/− mice have been published in tau models, Jiang and colleagues have conducted studies altering TREM2 expression in vivo by lentiviral overexpression (under a Cd11b promoter) or shRNA knockdown [50, 51] in the P301S tau transgenic model.”
Background
Neuroinflammation in Alzheimer’s Disease: from Pathogenesis to a Therapeutic Target
Pimplikar, S. W. (2014) · Journal of Clinical Immunology · doi:10.1007/s10875-014-0032-5 · Cited by 106 · cited 1×
“Besides Aβ, intracellular tangles of hyperphosphorylated tau proteins are the other major pathological component of AD [49].”
Background
Common themes in the assembly and architecture of activating immune receptors
Call, M., & Wucherpfennig, K. (2007) · Nature reviews. Immunology · doi:10.1038/nri2186 · Cited by 102 · cited 1×
“The interaction with the receptor is important to shield the polar residues from the lipophilic membrane environment and to allow trafficking to the cell surface (reviewed in [84]).”
Background
Structural Basis for Plexin Activation and Regulation
Kong, Y., Janssen, B. J., Malinauskas, T., Vangoor, V., Coles, C. H., Kaufmann, R., Ni, T., Gilbert, R. J. C., Padilla-Parra, S., Pasterkamp, R., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.018 · Cited by 99
Homozygous TREM2 mutation in a family with atypical frontotemporal dementia
Ber, I. L., de Septenville, A. L., Guerreiro, R. J., Brás, J., Camuzat, A., Caroppo, P., Lattante, S., Couarch, P., Kabashi, E., Bouya-Ahmed, K., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.04.010 · Cited by 99
Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice
Jiang, T., Yu, J., Zhu, X., Tan, M., Gu, L.-Z., Zhang, Y., & Tan, L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.026 · Cited by 97
Disease‐Associated Mutations of TREM2 Alter the Processing of N‐Linked Oligosaccharides in the Golgi Apparatus
Park, J., Ji, I. J., An, H. J., Kang, M., Kang, S., Kim, D., & Yoon, S. (2015) · Traffic · doi:10.1111/tra.12264 · Cited by 90 · cited 2×
“Slightly altered glycosylation patterns have been observed for the R47H variant [27, 28], but it is unclear if these have functional ramifications.”
Background
Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance
Chen, Q., Zhang, K., Jin, Y., Zhu, T., Cheng, B., Shu, Q., & Fang, X. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201211-1967oc · Cited by 87
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Promotes Adipogenesis and Diet-Induced Obesity
Park, M. S., Yi, J., Kim, E. M., Yoon, I.-J., Lee, E. H., Lee, H.-Y., Ji, K.-Y., Lee, K. H., Jang, J.-H., Oh, S.-S., et al. (2014) · Diabetes · doi:10.2337/db13-1869 · Cited by 85
Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility
Liu, G., Liu, Y., Jiang, Q., Jiang, Y., Feng, R., Zhang, L., Chen, Z., Li, K., & Liu, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9416-7 · Cited by 85 · cited 1×
“Beyond AD, TREM2 variants have been linked to other neurodegenerative diseases, including Parkinson’s disease [20, 21] and sporadic amyotrophic lateral sclerosis (ALS) [22], and fronto-temporal dementia [23, 24], though these non-AD associations have not been as widely reproduced [16].”
Background
Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4
Tietjen, G. T., Gong, Z., Chen, C.-H., Vargas, E., Crooks, J. E., Cao, K. D., Heffern, C. T. R., Henderson, J. M., Mati Meron, E., Lin, B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320174111 · Cited by 83
Initial characterization of TREM-like transcript (TLT)-1: a putative inhibitory receptor within the TREM cluster.
Washington, A., Quigley, L., & McVicar, D. (2002) · Blood · doi:10.1182/blood-2002-02-0523 · Cited by 80 · cited 1×
“Finally, TREM-like transcript 1, (TREML1, also TLT-1), an ITIMcontaining member of the TREM family is expressed in bone tissue [95] and associates with the tyrosine phosphatase SHP-1 upon phosphorylation.”
Background
The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective
Humphrey, M. B., Xing, J., & Titus, A. (2015) · Research and Reports in Biochemistry · doi:10.2147/rrbc.s58057 · Cited by 77
Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12
Inui, M., Kikuchi, Y., Aoki, N., Endo, S., Maeda, T., Sugahara–Tobinai, A., Fujimura, S., Nakamura, A., Kumanogoh, A., Colonna, M., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900463106 · Cited by 77 · cited 2×
“While it is established that DAP12 requires complexing with a receptor for trafficking to the cell surface, there have been multiple reports of TREM2 surface expression in Dap12 and Dap12/Dap10-deficient cells [71, 85, 86].”
Background
The Structure of the Extracellular Domain of Triggering Receptor Expressed on Myeloid Cells Like Transcript-1 and Evidence for a Naturally Occurring Soluble Fragment*
Gattis, J. L., Washington, A., Chisholm, M., Quigley, L., Szyk, A., McVicar, D., & Lubkowski, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600489200 · Cited by 75
Triggering receptor expressed on myeloid cells‐2 fine‐tunes inflammatory responses in murine Gram‐negative sepsis
Gawish, R., Martins, R., Boehm, B., Wimberger, T., Sharif, O., Lakovits, K., Schmidt, M., & Knapp, S. (2014) · The FASEB Journal · doi:10.1096/fj.14-260067 · Cited by 73
TREM‐2 Promotes Macrophage‐Mediated Eradication of Pseudomonas aeruginosa via a PI3K/Akt Pathway
Zhu, M., Li, D., Wu, Y., Huang, X., & Wu, M. (2014) · Scandinavian Journal of Immunology · doi:10.1111/sji.12148 · Cited by 67 · cited 4×
“Cellular studies have shown that TREM2 regulates the response to bacteria, in two examples by promoting killing of bacteria through production of reactive oxygen species (ROS) [75, 76] – even against bacteria that were not directly detected by TREM2 [75].”
BackgroundInfluential
TREM-2 Promotes Host Resistance Against Pseudomonas aeruginosa Infection by Suppressing Corneal Inflammation via a PI3K/Akt Signaling Pathway
Sun, M., Zhu, M., Chen, K., Nie, X., Deng, Q., Hazlett, L. D., Wu, Y., Li, M., Wu, M., & Huang, X. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-10938 · Cited by 66
Extracellular Heat Shock Proteins: Alarmins for the Host Immune System
Wheeler, D. S. (2011) · The Open Inflammation Journal · doi:10.2174/1875041901104010049 · Cited by 65
A Physical Interaction Between the Adaptor Proteins DOK3 and DAP12 Is Required to Inhibit Lipopolysaccharide Signaling in Macrophages
Peng, Q., Long, C. L., Malhotra, S., & Humphrey, M. B. (2013) · Science Signaling · doi:10.1126/scisignal.2003801 · Cited by 64
Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response
O'Callaghan, P. W., Li, J., Lannfelt, L., Lindahl, U., & Zhang, X. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.634337 · Cited by 58
Evidence for TLR4 and FcRγ–CARD9 activation by cholera toxin B subunit and its direct bindings to TREM2 and LMIR5 receptors
Phongsisay, V., Iizasa, E., Hara, H., & Yoshida, H. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.05.008 · Cited by 56
The Innate Immune Response toSalmonella entericaSerovar Typhimurium by Macrophages Is Dependent on TREM2-DAP12
Charles, J. F., Humphrey, M. B., Zhao, X., Quarles, E. K., Nakamura, M. C., Aderem, A. A., Seaman, W. E., & Smith, K. D. (2008) · Infection and Immunity · doi:10.1128/iai.00115-08 · Cited by 54 · cited 4×
“Cellular studies have shown that TREM2 regulates the response to bacteria, in two examples by promoting killing of bacteria through production of reactive oxygen species (ROS) [75, 76] – even against bacteria that were not directly detected by TREM2 [75].”
BackgroundInfluential
TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells
Quan, D. N., Cooper, M. D., Potter, J. L., Roberts, M. H., Cheng, H., & Jarvis, G. A. (2008) · Mucosal Immunology · doi:10.1038/mi.2008.1 · Cited by 53
The Alzheimer's Disease-Associated R47H Variant of TREM2 Has an Altered Glycosylation Pattern and Protein Stability
Park, J., Ji, I. J., Kim, D., An, H. J., & Yoon, S. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00618 · Cited by 48 · cited 1×
“Slightly altered glycosylation patterns have been observed for the R47H variant [27, 28], but it is unclear if these have functional ramifications.”
Background
TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice
Jiang, T., Wan, Y., Zhang, Y.-D., Zhou, J.-S., Gao, Q., Zhu, X.-C., Shi, J.-Q., Lu, H., Tan, L., & Yu, J.-T. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-9704-x · Cited by 46
Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1
Félix, J., Munck, S. D., Verstraete, K., Meuris, L., Callewaert, N., Elegheert, J., & Savvides, S. N. (2015) · Structure · doi:10.1016/j.str.2015.06.019 · Cited by 45
Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains
Zhu, C., Herrmann, U. S., Li, B., Abakumova, I., Moos, R., Schwarz, P., Rushing, E. J., Colonna, M., & Aguzzi, A. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.02.019 · Cited by 44
Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2)
Glebov, K., Wunderlich, P., Karaca, I., & Walter, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0479-9 · Cited by 44 · cited 1×
“While it is well-established that metalloproteases can cleave the TREM2 stalk to liberate the Ig domain [2, 25, 55], whether this function belongs to a specific protease in the human brain is unclear.”
Background
A case of possible autoimmune bilateral vestibulopathy treated with steroids
Schüler, O. G. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.6.825 · Cited by 40
Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease
Golde, T. E., Streit, W. J., & Chakrabarty, P. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt178 · Cited by 39 · cited 1×
“TREM2 AD risk variants are rare, but carry roughly the same risk as a copy of the apolipoprotein E4 (APOE4) allele and clearly link the innate immune system to neurodegenerative disease [19].”
Background
DDR2 (discoidin domain receptor 2) suppresses osteoclastogenesis and is a potential therapeutic target in osteoporosis
Zhang, Y., Su, J., Wu, S., Teng, Y., Yin, Z., Guo, Y., Li, J., Li, K., Yao, L., & Li, X. (2015) · Science Signaling · doi:10.1126/scisignal.2005835 · Cited by 35
The Linker for Activation of B Cells (LAB)/Non-T Cell Activation Linker (NTAL) Regulates Triggering Receptor Expressed on Myeloid Cells (TREM)-2 Signaling and Macrophage Inflammatory Responses Independently of the Linker for Activation of T Cells
Whittaker, G. C., Orr, S. J., Quigley, L., Hughes, L., Francischetti, I. M. B., Zhang, W., & McVicar, D. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.038398 · Cited by 33 · cited 22×
“LAB−/− macrophages display increased ERK phosphorylation following TLR stimulation [92].”
BackgroundInfluential
Triggering Receptor Expressed on Myeloid Cells-2 Correlates to Hypothermic Neuroprotection in Ischemic Stroke
Kawabori, M., Hokari, M., Zheng, Z., Kim, J. Y., Calosing, C., Hsieh, C. L., Nakamura, M. C., & Yenari, M. A. (2013) · Therapeutic Hypothermia and Temperature Management · doi:10.1089/ther.2013.0020 · Cited by 32 · cited 1×
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
Background
Apo E: The role of conserved residues in defining function
Frieden, C. (2015) · Protein Science · doi:10.1002/pro.2597 · Cited by 29
TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis*
Yoon, S.-H., Lee, Y. D., Ha, J., Lee, Y., & Kim, H.-H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.351239 · Cited by 28 · cited 2×
“The structural basis for these interactions are not known, and they may be indirect through association with signaling complexes [96].”
Background
NMR Observable-Based Structure Refinement of DAP12-NKG2C Activating Immunoreceptor Complex in Explicit Membranes
Cheng, X., & Im, W. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.03.002 · Cited by 28
The Association of Polar Residues in the DAP12 homodimer: TOXCAT and Molecular Dynamics Simulation Studies
Wei, P., Zheng, B.-K., Guo, P.-R., Kawakami, T., & Luo, S. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.01.054 · Cited by 24
The role of TREM-2 in internalization and intracellular survival of Brucella abortus in murine macrophages
Wei, P., Lü, Q., Cui, G., Guan, Z., Li, Y., Sun, C., Sun, W., & Peng, Q. (2014) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2014.12.007 · Cited by 21 · cited 1×
“abortus, [77] a pathogen that specializes in invading and surviving in macrophages.”
Background
LAB/NTAL/ Lat2 : a force to be reckoned with in all leukocytes?
Orr, S. J., & McVicar, D. W. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0410221 · Cited by 19 · cited 4×
“Whittaker GC, Orr SJ, Quigley L, Hughes L, Francischetti IM, Zhang W, et al. The linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) regulates triggering receptor expressed on myeloid cells (TREM)-2 signaling and macrophage inflammatory responses independently of the linker for activation of T c…”
BackgroundInfluential
3-O-sulfo-β-d-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5
Phongsisay, V., Iizasa, E., Hara, H., & Yamasaki, S. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.07.023 · Cited by 18
Campylobacter jejuni targets immunoglobulin-like receptor LMIR5.
Phongsisay, V. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2014.07.024 · Cited by 15
Reduced Glycosaminoglycan Sulfation Diminishes the Agrin Signal Transduction Pathway
Mcdonnell, K., & Grow, W. A. (2004) · Developmental Neuroscience · doi:10.1159/000080706 · Cited by 15

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Sorted by citations

Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668
“In the CNS, TREM2 can interact with a range of ligands, but it is mostly known as a receptor for lipid substrates.(210) For example, APOE, ApoJ/CLU, Galectin-3, lipidated Aβ as well as lipids exposed on the surface of apoptotic cells can bind with TREM2 and activate it.”
Background
The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway
Deczkowska, A., Weiner, A., & Amit, I. (2020) · Cell · doi:10.1016/j.cell.2020.05.003 · Cited by 648
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441
TREM2 in Neurodegenerative Diseases
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].”
Background
TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice
Chen, S., Peng, J., Sherchan, P., Ma, Y., Xiang, S., Yan, F., Zhao, H., Jiang, Y. Q., Wang, N., Zhang, J. H., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01853-x · Cited by 392
“Triggering receptor expressed on myeloid cells 2 (TREM2) is an important innate immune receptor, which belongs to the lectin-like immunoglobulin superfamily and is primarily expressed on myeloid cells, such as immature dendritic cells, osteoclasts, tissue macrophages, and microglia [11, 12].”

See all 284

Authors: Kober, D. L., & Brett, T. J.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Brett, Tom J.
ORCID: Kober, Daniel L.
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)
DOI: 10.1016/j.jmb.2017.04.004
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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TREM2-Ligand Interactions in Health and Disease

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