TREMs in the immune system and beyond

Colonna, Marco

doi:10.1038/nri1106

Cited by 701Inflammation biomarkers and pathwaysImmune Response and InflammationNeuroinflammation and Neurodegeneration Mechanisms

TREMs in the immune system and beyond

Colonna, Marco·2003·Nature Reviews Immunology

DOI 10.1038/nri1106

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Abstract

Triggering receptors expressed by myeloid cells (TREMs) belong to a rapidly expanding family of receptors that include activating and inhibitory isoforms encoded by a gene cluster linked to the MHC. TREM1 and TREM2 activate myeloid cells by signalling through the adaptor protein DAP12. TREM1 triggers phagocyte secretion of pro-inflammatory chemokines and cytokines, amplifying the inflammation that is induced by bacteria and fungi. TREM2 activates monocyte-derived dendritic cells and regulates osteoclast development. Remarkably, TREM2 deficiency leads to a severe disease that is characterized by bone cysts and demyelination of the central nervous system, which results in dementia, implying that the function of TREM2 extends beyond the immune system.

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Loss of function mutations in TREM2 are risk factors for ALS.
“loss of function mutations in TREM2 (triggering receptor expressed on myeloid cells 2), which affect microglia phagocytosis and inflammation, are risk factors for ALS [425–427]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [426]
Microglia play a pivotal role in ALS pathogenesis.
“confirming the pivotal role played by microglia in ALS pathogenesis.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [426]
The BAC transgene design deletes essential exons in three other TREM-like genes, which have important innate immunity functions and may play distinct roles in AD.
“An important aspect of our BAC transgene design is the deletion of essential exons in three other TREM-like genes on the BAC, which are known to have important innate immunity function (Colonna, 2003; Ford and McVicar, 2009), and may play distinct roles in AD (Carrasquillo et al., 2017).”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Colonna, 2003

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Untitled work
Kalina (2002) · doi:10.1002/1521-4141(200209)32:9
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Daws (2001) · doi:10.1002/1521-4141(200103)31:3

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Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · see citing works
Alveolar macrophages: plasticity in a tissue-specific context
Hussell, T., & Bell, T. J. (2014) · Nature Reviews Immunology · doi:10.1038/nri3600 · Cited by 1,377 · see citing works
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357 · see citing works
MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION
Taylor, P. R., Martínez‐Pomares, L., Stacey, M. A., Lin, H.-H., Brown, G. D., & Gordon, S. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115816 · Cited by 1,325 · see citing works
Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124 · see citing works
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.2016.05.003 · Cited by 817 · see citing works
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Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., et al. (2004) · Nature · doi:10.1038/nature02444 · Cited by 828 · see citing works
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798 · see citing works
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Neuronal ‘On’ and ‘Off’ signals control microglia
Biber, K., Neumann, H., Inoue, K., & Boddeke, H. W. G. M. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.08.007 · Cited by 787 · see citing works
Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response
Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza‐Serrano, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00488 · Cited by 706 · see citing works
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models
Jay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · see citing works
The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity
Filipello, F., Morini, R., Corradini, I., Zerbi, V., Canzi, A., Michalski, B., Erreni, M., Markicevic, M., Starvaggi-Cucuzza, C., Otero, K., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.016 · Cited by 695 · see citing works
New insights on the role of microglia in synaptic pruning in health and disease
Hong, S., Dissing-Olesen, L., & Stevens, B. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.12.004 · Cited by 557 · see citing works
Osteoimmunology: Interactions of the Bone and Immune System
Lorenzo, J., Horowitz, M. C., & Choi, Y. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0038 · Cited by 566 · see citing works
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · see citing works
“However, TREM2 has classically been described as modestly antiinflammatory and loss of function has also been shown to reduce the same inflammatory markers, such as IL-1β and TNF-α, in other studies (21, 39).”
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The development and function of lung-resident macrophages and dendritic cells
Kopf, M., Schneider, C., & Nobs, S. P. (2015) · Nature Immunology · doi:10.1038/ni.3052 · Cited by 555 · see citing works
Siglecs—the major subfamily of I-type lectins
Varki, A. P., & Angata, T. (2005) · Glycobiology · doi:10.1093/glycob/cwj008 · Cited by 518 · see citing works
Mouse models of inflammatory bowel disease☆
Wirtz, S. J., & Neurath, M. F. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.07.003 · Cited by 508 · see citing works
A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia
Hsieh, C. L., Koike, M., Spusta, S. C., Niemi, E. C., Yenari, M., Nakamura, M. C., & Seaman, W. E. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06042.x · Cited by 475 · see citing works
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2110-16.2016 · Cited by 457 · see citing works
Alzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440 · see citing works
Migration of Dendritic Cell Subsets and their Precursors
Randolph, G. J., Ochando, J., & Partida‐Sánchez, S. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090254 · Cited by 468 · see citing works
Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449 · see citing works
Cutting Edge: Inhibition of TLR and FcR Responses in Macrophages by Triggering Receptor Expressed on Myeloid Cells (TREM)-2 and DAP12
Hamerman, J. A., Jarjoura, J. R., Humphrey, M. B., Nakamura, M. C., Seaman, W. E., & Lanier, L. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.4.2051 · Cited by 440 · see citing works
Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models
Lee, C. Y. D., Daggett, A., Gu, X., Jiang, L.-L., Langfelder, P., Li, X., Wang, N., Zhao, Y., Park, C. S., Cooper, Y., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.002 · Cited by 396 · see citing works
Roles of microglia in brain development, tissue maintenance and repair
Michell‐Robinson, M. A., Touil, H., Healy, L. M., Owen, D. R., Durafourt, B. A., Bar‐Or, A., Antel, J. P., & Moore, C. S. (2015) · Brain · doi:10.1093/brain/awv066 · Cited by 421 · 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
TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease
Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-19 · Cited by 404 · see citing works
TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis
Takahashi, K., Prinz, M., Stagi, M., Chechneva, O., & Neumann, H. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040124 · Cited by 414 · see citing works
Plasma Level of a Triggering Receptor Expressed on Myeloid Cells-1: Its Diagnostic Accuracy in Patients with Suspected Sepsis
Gibot, S., Kolopp‐Sarda, M., Béné, M. C., Cravoisy, A., Lévy, B., Faure, G. C., & Bollaert, P. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-141-1-200407060-00009 · Cited by 403 · see citing works
Semaphorins and their receptors in immune cell interactions
Suzuki, K., Kumanogoh, A., & Kikutani, H. (2008) · Nature Immunology · doi:10.1038/ni1553 · Cited by 400 · see citing works
Ontogeny and homeostasis of CNS myeloid cells
Prinz, M., Erny, D., & Hagemeyer, N. (2017) · Nature Immunology · doi:10.1038/ni.3703 · Cited by 391 · see citing works
Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.579 · Cited by 374 · see citing works
Microglial Activation in Stroke: Therapeutic Targets
Yenari, M. A., Kauppinen, T. M., & Swanson, R. A. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.07.005 · Cited by 390 · see citing works
Do glia drive synaptic and cognitive impairment in disease?
Chung, W.-S., Welsh, C. A., Barres, B. A., & Stevens, B. (2015) · Nature Neuroscience · doi:10.1038/nn.4142 · Cited by 385 · see citing works
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., Calosing, C., Kim, J. Y., Hsieh, C. L., Nakamura, M. C., & Yenari, M. A. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2620-14.2015 · Cited by 375 · see citing works
TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · see citing works
Factors regulating microglia activation
Kierdorf, K., & Prinz, M. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00044 · Cited by 360 · see citing works
A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis
Gibot, S., Kolopp‐Sarda, M., Béné, M.-C., Bollaert, P., Lozniewski, A., Mory, F., Lévy, B., & Faure, G. C. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040708 · Cited by 361 · see citing works
The role of the immune system in the pathophysiology of osteoporosis
Clowes, J. A., Riggs, B. L., & Khosla, S. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00334.x · Cited by 361 · see citing works
Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease
Ewers, M., Franzmeier, N., Suárez-Calvet, M., Morenas-Rodriguez, E., Caballero, M. A. A., Kleinberger, G., Piccio, L., Cruchaga, C., Deming, Y., Dichgans, M., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav6221 · Cited by 327 · see citing works
The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors
Hara, H., Ishihara, C., Takeuchi, A., Imanishi, T., Xue, L., Morris, S. W., Inui, M., Takai, T., Shibuya, A., Saijo, S., et al. (2007) · Nature Immunology · doi:10.1038/ni1466 · Cited by 351 · see citing works
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status
Piccio, L., Deming, Y., Del-Águila, J. L., Ghezzi, L., Holtzman, D. M., Fagan, A. M., Fenoglio, C., Galimberti, D., Borroni, B., & Cruchaga, C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1533-5 · Cited by 337 · see citing works
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
Bemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0216-6 · Cited by 299 · see citing works
Elucidating the Role of TREM2 in Alzheimer’s Disease
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.042 · Cited by 325 · see citing works
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Immune Regulation in the Aging Retina
Chen, M., Luo, C., Zhao, J., Devarajan, G., & Xu, H. (2019) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.10.003 · Cited by 305 · see citing works
TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway
Zheng, H., Jia, L., Liu, C.-C., Rong, Z., Zhong, L., Yang, L., Chen, X.-F., Fryer, J. D., Wang, X., Zhang, Y.-W., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2459-16.2017 · Cited by 317 · see citing works
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911227 · Cited by 324 · see citing works
Two Unique Human Decidual Macrophage Populations
Houser, B. L., Tilburgs, T., Hill, J. A., Nicotra, M. L., & Strominger, J. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003153 · Cited by 324 · see citing works
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 · see citing works
Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease
Jiang, T., Tan, L., Zhu, X.-C., Zhang, Q.-Q., Cao, L., Tan, M.-S., Gu, L.-Z., Wang, H.-F., Ding, Z.-Z., Zhang, Y.-D., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.164 · Cited by 320 · see citing works
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296 · see citing works
Microglial clearance function in health and disease
Napoli, I., & Neumann, H. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.06.046 · Cited by 312 · see citing works
Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517540 · Cited by 296 · see citing works
Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease
Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., Öhrfelt, A., Blennow, K., Hardy, J., Schott, J., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0071-x · Cited by 303 · see citing works
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 · see citing works
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Neuroinflammation in frontotemporal dementia
Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0231-z · Cited by 280 · see citing works
TREM2-Ligand Interactions in Health and Disease
Kober, D. L., & Brett, T. J. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.04.004 · Cited by 284 · see citing works
“In contrast with TREM1, which signals through DAP12 to amplify TLR responses [97], TREM2 inhibits inflammatory cytokine production following TLR stimulation in cultured BMDMs and DCs [98–100].”
Background
Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer
Wu, Q., Zhou, W., Yin, S., Zhou, Y., Chen, T., Qian, J., Su, R., Hong, L., Lu, H., Zhang, F., et al. (2019) · Hepatology · doi:10.1002/hep.30593 · Cited by 268 · see citing works
Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke
Xu, P., Zhang, X., Liu, Q., Xie, Y., Shi, X., Chen, J., Li, Y., Guo, H., Sun, R., Hong, Y., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1777-9 · Cited by 270 · see citing works
Immune aging, dysmetabolism, and inflammation in neurological diseases
Deleidi, M., JÃ¤ggle, M., & Rubino, G. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00172 · Cited by 260 · see citing works
TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives
Tammaro, A., Derive, M., Gibot, S., Leemans, J. C., Florquin, S., & Dessing, M. C. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.043 · Cited by 252 · see citing works
The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
Cheng-Hathaway, P. J., Reed-Geaghan, E. G., Jay, T. R., Casali, B. T., Bemiller, S. M., Puntambekar, S. S., von Saucken, V. E., Williams, R. Y., Karlo, J. C., Moutinho, M., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0262-8 · Cited by 252 · 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 · see citing works
Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis
Neumann, H., & Takahashi, K. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.032 · Cited by 249 · see citing works
Innate and adaptive immunity: specificities and signaling hierarchies revisited
Vivier, É., & MALISSEN, B. (2004) · Nature Immunology · doi:10.1038/ni1153 · Cited by 246 · see citing works
Role of ITAM‐containing adapter proteins and their receptors in the immune system and bone
Humphrey, M. B., Lanier, L. L., & Nakamura, M. C. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00325.x · Cited by 241 · see citing works
The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
Wu, J., Li, J., Salcedo, R., Mivechi, N. F., Trinchieri, G., & Horuzsko, A. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0938 · Cited by 238 · see citing works
TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors
Arts, R. J. W., Joosten, L. A. B., van der Meer, J. W. M., & Netea, M. G. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0312145 · Cited by 234 · see citing works
Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses
Hashiguchi, M., Kobori, H., Ritprajak, P., Kamimura, Y., Kozono, H., & Azuma, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802423105 · Cited by 225 · see citing works
Fc Receptor-Like Molecules
Davis, R. S. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141541 · Cited by 225 · see citing works
Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO
Narayanaswami, V., Dahl, K., Bernard‐Gauthier, V., Josephson, L., Cumming, P. D., & Vasdev, N. (2018) · Molecular Imaging · doi:10.1177/1536012118792317 · Cited by 215 · see citing works
Transmembrane adaptor proteins: organizers of immunoreceptor signalling
Hořejšı́, V., Zhang, W., & Schraven, B. L. (2004) · Nature reviews. Immunology · doi:10.1038/nri1414 · Cited by 213 · see citing works
TREM2, microglia, and Alzheimer’s disease.
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TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
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“TREM2 and MerTK are coexpressed in plaque associated macrophages TREM2 is expressed exclusively by microglia in the brain, but also by peripheral monocytes and macrophages (Colonna, 2003).”
Background
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Self-citation

Authors: Colonna, M.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Colonna, Marco
ORCID: Colonna, Marco
Venue: Nature Reviews Immunology
Publisher: Springer Science and Business Media LLC
Published: 2003-06-01
Volume: 3
Issue: 6
Pages: 445-453
ISSN: 1474-1733 (ISSN-L)
1474-1741
DOI: 10.1038/nri1106
OpenAlex: W1986899130
Cited by: 701
References: 84
Citations by year: 2026: 20 · 2025: 36 · 2024: 39 · 2023: 39 · 2022: 35 · 2021: 42 · 2020: 31 · 2019: 34 · 2018: 30 · 2017: 43 · 2016: 43 · 2015: 34 · 2014: 33 · 2013: 36 · 2012: 19
FWCI: 2.12
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Academy of Sciences of Ukraine
Topics: Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: TREM-1, TREM2, DAP12, myeloid cell activation, innate immunity, inflammation, dendritic cells, osteoclast development, TREM2 deficiency, bone cysts, demyelination, dementia
MeSH terms: Triggering Receptor Expressed on Myeloid Cells-1, Animals, Bone Cysts, Cell Differentiation, Dendritic Cells, Humans, Inflammation, Membrane Glycoproteins, Membrane Proteins, Phagocytes, Receptors, Immunologic, Signal Transduction, Cytokines, Chemokines, Hereditary Central Nervous System Demyelinating Diseases, Myeloid Cells, Adaptor Proteins, Signal Transducing

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