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, as well as ApoE and lipidated Amyloid beta (Aβ).
“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]
In §3, “TREM2 binds anionic ligands on mammalian cells” (page unavailable), the review reports TREM2 binding to phospholipids in laboratory assays. It also reports increased binding to some apoptotic cells, but says it is unclear which ligand accounts for that binding; apoptotic Jurkat cells exposing phosphatidylserine did not bind Fc-TREM2. Thus, the cited source does not establish that the lipids exposed on apoptotic-cell surfaces are what TREM2 binds. The ApoE and Aβ clauses carry separate citations. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTREM2 associates with DAP12 to induce signal transduction, including recruitment and activation of SYK and calcium flux.
“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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“Instead, Trem2 deficiency was associated with decreased expression of lipid metabolism enzymes and a failure to degrade myelin debris [64, 65].”
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“TREM2 responds to tonic stimuli to regulate inflammation—TREM2 and DAP12 reduce inflammatory TLR signals [98, 99] in cultured BMDMs.”
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“) lacking known signaling or trafficking motifs [1].”
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“Indeed, TREM2 can bind primary macrophages [98] and DCs [100].”
BackgroundInfluentialTREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
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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).”
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“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].”
BackgroundThe 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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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].”
BackgroundPattern Recognition by TREM-2: Binding of Anionic Ligands
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“This tyrosine is part of a “closet ITIM” sequence which was previously hypothesized to mediate inhibitory signals (SPYQEL, canonical ITIM is S/I/V/LxYxxI/V/L) [93].”
BackgroundEfficient colonic mucosal wound repair requires Trem2 signaling
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“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].”
BackgroundBlockade 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 · see citing works
Activating and inhibitory functions of DAP12
Turnbull, I. R., & Colonna, M. (2007) · Nature Reviews Immunology · doi:10.1038/nri2014 · Cited by 273 · see citing works
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× · see citing works
“While these possibilities are explored, CSF sTREM2 certainly has potential as a biomarker for microgliosis during AD onset [48]”
BackgroundInfluentialPlexin-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 · see citing works
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 · see citing works
<i>TREM2</i>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× · see citing works
“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].”
BackgroundImpaired 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× · see citing works
“Indeed, TREM2 can bind primary macrophages [98] and DCs [100].”
BackgroundInfluentialKlünemann, 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 · see citing works
DAP12-mediated Signal Transduction in Natural Killer Cells
McVicar, D., Taylor, L., Gosselin, P., Willette-Brown, J., Mikhael, A., Geahlen, R., Nakamura, M. C., Linnemeyer, P., Seaman, W., Anderson, S., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32934 · Cited by 249 · see citing works
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× · see citing works
“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].”
BackgroundTREM-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 242 · see citing works
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 · see citing works
Self-citationStructural basis of semaphorin–plexin signalling
Janssen, B. J., Robinson, R., Pérez-Brangulí, F., Bell, C. H., Mitchell, K., Siebold, C., & Jones, E. Y. (2010) · Nature · doi:10.1038/nature09468 · Cited by 236 · see citing works
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× · see citing works
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
BackgroundResultInfluentialImmunological 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 · see citing works
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× · see citing works
“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.”
BackgroundResultInfluentialTREM-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 · see citing works
The immunology of neurodegeneration
Czirr, E., & Wyss‐Coray, T. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58656 · Cited by 211 · cited 1× · see citing works
“Therefore, preventing or containing disease will require a more sophisticated understanding of the protective and pathogenic features of the inflammatory process [57].”
BackgroundMetalloproteinases 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 · see citing works
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× · see citing works
“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-citationCNS 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 · see citing works
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× · see citing works
“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].”
BackgroundThe structural basis for intramembrane assembly of an activating immunoreceptor complex
Call, M., Wucherpfennig, K., & Chou, J. (2010) · Nature Immunology · doi:10.1038/ni.1943 · Cited by 192 · see citing works
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. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.009 · Cited by 191 · cited 1× · see citing works
“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].”
BackgroundRao, N. L., Dodge, I., & Band, H. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.5.753 · Cited by 190 · cited 1× · see citing works
“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].”
BackgroundSimhadri, 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 189 · see citing works
TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis
Otero, K., Shinohara, M., Zhao, H.-B., Cella, M., Gilfillan, S., Colucci, A., Faccio, R., Ross, P. F., Teitelbaum, S. L., Takayanagi, H., et al. (2012) · Journal of Immunology · doi:10.4049/jimmunol.1102836 · Cited by 188 · see citing works
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× · see citing works
“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]).”
BackgroundTREM2 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 · see citing works
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 181 · see citing works
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× · see citing works
“Within the normal human brain, TREM2 is expressed most highly in white matter, with transcripts detected in all major areas [34].”
BackgroundTREM2 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× · see citing works
“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.”
BackgroundThe 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 · see citing works
Ito, H., & Hamerman, J. A. (2012) · European Journal of Immunology · doi:10.1002/eji.201141679 · Cited by 173 · cited 8× · see citing works
“Indeed, TREM2 can bind primary macrophages [98] and DCs [100].”
BackgroundInfluentialHeterozygous 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× · see citing works
“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].”
BackgroundSessa, 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× · see citing works
“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,…”
BackgroundInfluentialSpecific 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 162 · see citing works
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 · see citing works
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× · see citing works
“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].”
BackgroundGuerreiro, 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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 141 · see citing works
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 · see citing works
DAP12 Couples c-Fms Activation to the Osteoclast Cytoskeleton by Recruitment of Syk
Zou, W., Reeve, J., Liu, Y., Teitelbaum, S. L., & Ross, F. P. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.06.023 · Cited by 130 · see citing works
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× · see citing works
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
BackgroundResultMutations 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 120 · cited 1× · see citing works
“The TREM2 variants include splice site [7, 9] early stop sites [7, 10–12], and coding ectodomain mutations [7, 8, 13–15].”
BackgroundGispert, 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 114 · see citing works
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× · see citing works
“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.”
BackgroundNeuroinflammation 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 103 · cited 1× · see citing works
“Besides Aβ, intracellular tangles of hyperphosphorylated tau proteins are the other major pathological component of AD [49].”
BackgroundCommon 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× · see citing works
“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]).”
BackgroundStructural 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 · see citing works
Homozygous TREM2 mutation in a family with atypical frontotemporal dementia
Ber, I. L., de Septenville, A. D., Guerreiro, R., Bras, 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 98 · see citing works
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 · see citing works
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 88 · cited 2× · see citing works
“Slightly altered glycosylation patterns have been observed for the R47H variant [27, 28], but it is unclear if these have functional ramifications.”
BackgroundChen, 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 · see citing works
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 · see citing works
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 · see citing works
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 83 · cited 1× · see citing works
“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].”
BackgroundWashington, A., Quigley, L., & McVicar, D. (2002) · Blood · doi:10.1182/blood-2002-02-0523 · Cited by 80 · cited 1× · see citing works
“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.”
BackgroundSignal 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 78 · cited 2× · see citing works
“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].”
BackgroundThe TREM2-DAP12 signaling pathway in Nasu&ndash;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 · see citing works
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 · see citing works
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 72 · see citing works
Sun, M.-X., Zhu, M., Chen, K., Nie, X.-X., Deng, Q., Hazlett, L., Wu, Y.-J., Li, M., Wu, M.-H., & Huang, X. (2013) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.12-10938 · Cited by 71 · see citing works
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 66 · cited 4× · see citing works
“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].”
BackgroundInfluentialPeng, Q., Long, C. L., Malhotra, S., & Humphrey, M. B. (2013) · Science Signaling · doi:10.1126/scisignal.2003801 · Cited by 64 · see citing works
Extracellular Heat Shock Proteins: Alarmins for the Host Immune System
Wheeler, D. S. (2011) · The Open Inflammation Journal · doi:10.2174/1875041901104010049 · Cited by 64 · see citing works
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 · see citing works
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× · see citing works
“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].”
BackgroundInfluentialPhongsisay, V., Iizasa, E., Hara, H., & Yoshida, H. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.05.008 · Cited by 54 · see citing works
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 · see citing works
Park, J., Ji, I. J., Kim, D., An, H. J., & Yoon, S. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00618 · Cited by 47 · cited 1× · see citing works
“Slightly altered glycosylation patterns have been observed for the R47H variant [27, 28], but it is unclear if these have functional ramifications.”
BackgroundJiang, 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 · see citing works
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 · see citing works
Glebov, K., Wunderlich, P., Karaca, I., & Walter, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0479-9 · Cited by 44 · cited 1× · see citing works
“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.”
BackgroundStructure 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 44 · see citing works
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 · see citing works
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 38 · cited 1× · see citing works
“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].”
BackgroundZhang, 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 · see citing works
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× · see citing works
“LAB−/− macrophages display increased ERK phosphorylation following TLR stimulation [92].”
BackgroundInfluentialKawabori, 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× · see citing works
“Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68].”
BackgroundApo<scp>E</scp>: The role of conserved residues in defining function
Frieden, C. (2015) · Protein Science · doi:10.1002/pro.2597 · Cited by 29 · see citing works
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× · see citing works
“The structural basis for these interactions are not known, and they may be indirect through association with signaling complexes [96].”
BackgroundCheng, X., & Im, W. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.03.002 · Cited by 28
Wei, P., Zheng, B., Guo, P., Kawakami, T., & Luo, S.-Z. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.01.054 · Cited by 24 · see citing works
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× · see citing works
“abortus, [77] a pathogen that specializes in invading and surviving in macrophages.”
BackgroundPhongsisay, V., Iizasa, E., Hara, H., & Yamasaki, S. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2014.07.023 · Cited by 20 · see citing works
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× · see citing works
“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…”
BackgroundInfluentialCampylobacter jejuni targets immunoglobulin-like receptor LMIR5.
Phongsisay, V. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2014.07.024 · Cited by 15 · see citing works
Reduced Glycosaminoglycan Sulfation Diminishes the Agrin Signal Transduction Pathway
Mcdonnell, K., & Grow, W. A. (2004) · Developmental Neuroscience · doi:10.1159/000080706 · Cited by 15 · see citing works
Flagged first, then by citations
6 of the 161 references couldn’t be matched to a known paper.
Research works printed but not linked: 9
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Cited by
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 · see citing works
“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.”
BackgroundThe 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 · see citing works
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441 · see citing works
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 · see citing works
“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].”
BackgroundChen, S., Peng, J.-H., Sherchan, P., Ma, Y.-J., Xiang, S., Yan, F., Zhao, H., Jiang, Y., Wang, N., Zhang, J. H., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01853-x · Cited by 352 · see citing works
“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].”
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 · see citing works
“Phosphorylation of this domain leads to the recruitment of spleen tyrosine kinase (Syk), which in turn activates PI3K and Immunity 50, April 16, 2019 963 PLCg, which activate downstream signaling cascades that include ERK, AKT, NF-kB, and NFAT (Kober and Brett, 2017; McVicar et al., 1998; Mócsai et al., 2006; Mócsai…”
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 · see citing works
The <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · see citing works
“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 · see citing works
Shao, F., Wang, X., Wu, H., Wu, Q., & Zhang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.825086 · Cited by 250 · see citing works
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 · see citing works
Macrophage subsets in atherosclerosis as defined by single‐cell technologies
Willemsen, L., & de Winther, M. P. J. (2020) · The Journal of Pathology · doi:10.1002/path.5392 · Cited by 228 · see citing works
“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 217 · see citing works
“A diverse set of potential TREM2 ligands that are anionic or lipidic in nature have been proposed [29].”
BackgroundZhong, L., Sheng, X., Wang, W., Li, Y., Zhuo, R., Wang, K., Zhang, L., Hu, D.-D., Hong, Y., Chen, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.06.016 · Cited by 168 · see citing works
Feuerbach, D., Schindler, P., Barske, C., Joller, S., Beng-Louka, E., Worringer, K., Kommineni, S., Kaykas, A., Ho, D., Ye, C.-Y., et al. (2017) · bioRxiv · doi:10.1101/133751 · Cited by 161 · see citing works
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 · see citing works
“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 · see citing works
“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 151 · see citing works
“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).”
BackgroundMicroglia-Specific Metabolic Changes in Neurodegeneration
Aldana, B. I. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.03.006 · Cited by 153 · see citing works
“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].”
BackgroundFlores-Dorantes, M. T., Díaz‐López, Y. E., & Gutiérrez‐Aguilar, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00863 · Cited by 159 · see citing works
Lannes, N., Eppler, E., Etemad, S., Yotovski, P., & Filgueira, L. (2017) · Oncotarget · doi:10.18632/oncotarget.23106 · Cited by 139 · see citing works
Yan, J., Zhang, Y., Wang, L., Zhao, L., Tang, S., Wang, Y., Gu, N., Sun, X., & Li, L. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02651-3 · Cited by 144 · see citing works
“The ligands of TREM2 include bacterial products, DNA, lipoproteins, and phospholipids [24].”
BackgroundGong, S., Zhai, M., Shi, J.-Y., Yu, G., Lei, Z.-J., Shi, Y.-F., Zeng, Y.-X., Ju, P.-Q., Yang, N., Zhang, Z., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-023-01252-8 · Cited by 120 · see citing works
“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 129 · see citing works
TREM2 ectodomain and its soluble form in Alzheimer’s disease
Yang, J., Fu, Z., Zhang, X., Xiong, M., Meng, L., & Zhang, Z. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01878-2 · Cited by 113 · see citing works
“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 · see citing works
“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 112 · see citing works
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 105 · see citing works
Desale, S. E., Chidambaram, H., & Chinnathambi, S. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00036-1 · Cited by 99 · see citing works
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 102 · see citing works
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 · see citing works
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 105 · see citing works
“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 95 · see citing works
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 96 · see citing works
“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 81 · see citing works
“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 87 · see citing works
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 · see citing works
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 89 · see citing works
“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…”
BackgroundPuntambekar, S. S., Saber, M., Lamb, B. T., & Kokiko‐Cochran, O. N. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.03.033 · Cited by 78 · see citing works
“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 85 · see citing works
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 · see citing works
“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 78 · see citing works
“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 · see citing works
“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 70 · see citing works
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 · see citing works
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 63 · see citing works
“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 · see citing works
“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 57 · see citing works
“The TREM2 R47H variant loses cE recognition capacity, causing lipid droplet dysmetabolism and impaired remyelination (15,76,137,138).”
Cao, Y., Zhao, L., Chen, Z., & Li, S. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1430465 · Cited by 58 · see citing works
Chernick, D., Ortiz-Valle, S., Jeong, A., Qu, W., & Li, L. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134306 · Cited by 54 · see citing works
Troutman, T. D., Kofman, E. R., & Glass, C. K. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.004 · Cited by 60 · see citing works
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 70 · see citing works
“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 57 · see citing works
“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 52 · see citing works
“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 · see citing works
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 56 · see citing works
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 50 · see citing works
“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 69 · see citing works
“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 48 · see citing works
“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 · see citing works
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 51 · see citing works
“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 61 · see citing works
“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 48 · see citing works
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 44 · see citing works
“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 · see citing works
The therapeutic potential of TREM2 in cancer
Wolf, E. M., Fingleton, B., & Hasty, A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.984193 · Cited by 40 · see citing works
“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 49 · see citing works
Dean, H. B., Roberson, E. D., & Song, Y. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01252 · Cited by 43 · see citing works
“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 39 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
Bennett, J. P., Keeney, P. M., & Brohawn, D. G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00235 · Cited by 38 · see citing works
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 37 · see citing works
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 52 · see citing works
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 43 · see citing works
“(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 · see citing works
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 52 · see citing works
“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 · see citing works
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 37 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 33 · see citing works
“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 36 · see citing works
“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 17 · see citing works
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 · see citing works
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 32 · see citing works
“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., Washington, M., Leung, D. W., Song, Y., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00795-9 · Cited by 39 · see citing works
“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
Guha-Ray, A., Odum, O., Wiseman, D., & Weinstock, A. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1147434 · Cited by 29 · see citing works
“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 33 · see citing works
“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 37 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
- 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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