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TREM2

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TREM2
Identifiers
AliasesTREM2, TREM-2, Trem2a, Trem2b, Trem2c, triggering receptor expressed on myeloid cells 2, PLOSL2
External IDsOMIM: 605086; MGI: 1913150; HomoloGene: 10352; GeneCards: TREM2; OMA:TREM2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

54209

83433

Ensembl

ENSG00000095970

ENSMUSG00000023992

UniProt

Q9NZC2

Q99NH8

RefSeq (mRNA)

NM_001271821
NM_018965

NM_001272078
NM_031254

RefSeq (protein)

NP_001258750
NP_061838

NP_001259007
NP_112544

Location (UCSC)Chr 6: 41.16 – 41.16 MbChr 17: 48.65 – 48.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein that in humans is encoded by the TREM2 gene.[5][6][7] TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia,[8] which are immune cells in the central nervous system.[9] In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury.[10] In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage.[11] TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

Gene

[edit]

The TREM2 gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding exon regions.[12][13] Alternative splicing of the TREM2 mRNA transcript leads to different isoforms of the protein being produced upon translation.[12] Specifically, TREM2 mRNA has 3 different isoforms containing 3 consistent exons, and 2 that vary between the isoforms.[14] TREM2 mRNA is most highly expressed in brain, lungs, adrenal glands, placenta, gall bladder, and colon.[12] The functions of TREM2 have been studied in mice with disruption or mutation of the mouse ortholog, Trem2.[15] TREM2 orthologs are also present in rat, dog, Rhesus monkey, macaque, chimpanzee, and other animals.[16]

Protein

[edit]
The TREM2 receptor with the ADAM10 and ADAM17 enzymes that create the soluble TREM2 fragment. Created with BioRender.com

The TREM2 receptor is a transmembrane protein that is made up of an extracellular region (also referred to as the ectodomain), the membrane-traversing segment, and an intracellular component.[17] The extracellular component of TREM2 can bind different anionic ligands, specifically glycoproteins and lipids.[18][19] This ectodomain component includes an Ig-like V-type domain, where ligands bind the receptor.[20] The TREM2 ectodomain is modified after protein translation; these modifications affect its affinity for different ligands.[14] The intracellular component of TREM2 does not have any signaling ability on its own; rather, it signals via the DNAX activator proteins 10 and 12 (DAP10 and DAP12). A single TREM2 molecule can interact with DAP10 and DAP12 at the same time.[19]

Part of the ectodomain of TREM2 can be processed by enzymes (ADAM10, ADAM17) and released as a soluble version, called soluble TREM2 (sTREM2).[14] This protein fragment is released into the serum and cerebral spinal fluid (CSF), and might serve as a biomarker for neurodegenerative and other disorders, but further studies are needed.[14]

Function

[edit]
TREM2 structure as identified with X-ray crystallography. Image available through RCSB PDB.[21]

The TREM2 protein is found in immune cells termed myeloid cells, which include macrophages, granulocytes, monocytes, and dendritic cells.[22] Monocyte-, macrophage-, and neutrophil-mediated inflammatory responses can be stimulated through G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14, toll like receptors (such as TLR4), and cytokine receptors (e.g., IFNGR1).[23][24] Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the immunoglobulin (Ig) superfamily, such as TREM2, or to the C-type lectin superfamily.[23][25]

On myeloid cells, TREM2 binds anionic molecules, free and bound to plasma membrane, including bacterial products, DNA, lipoproteins, phospholipids, glycoproteins, DNA, and bacterial fragments.[13][18][19][26][27] TREM2 binding of ligand results in phosphorylation at 2 tyrosines in the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12 by SRC tyrosine kinases.[19] Spleen tyrosine kinase (Syk) interacts with these phosphorylation sites and activates the phosphatidylinositol-3 kinase (PI3K) signaling pathway, as well as other signaling molecules such as mTOR, MAPK, and ERK.[19][28] Association of TREM2 with DAP10 also activates the PI3K signaling pathway,[29] leading to expression of transcription factors that include AP1, NF-κB, and NFAT.[28] The PI3K signaling pathway also increases intracellular calcium content, which activates calcium-dependent kinases.[28][29] TREM2 activation also affects expression of GAL1, GAL3, IL1RN, and progranulin, which modulate the immune response.[19]

TREM2 is expressed by microglia[30] and osteoclasts, and is involved in development and/or maintenance of brain and bone.[19] In mice, TREM2 is involved in synaptic pruning, a process of shaping neuronal circuitry by microglia- and astrocyte-mediated removal of excessive synapses via phagocytosis.[14][31][32] In brain, the highest levels of TREM2 are found in hippocampus, white matter, and the spinal cord, and levels of TREM2 increase with age in humans and mice.[30] TREM2 is also expressed by macrophages of adipose tissue, adrenal gland, and placenta.[19]

Immunosuppressive tumor-associated macrophages (TAMs) have been characterized by expression of TREM2.[33] TREM2 signaling leads to downregulated transcription of genes that promote inflammation (Tnf, Il1b, and Nos2),[34] as well as release of cytokines that prevent activation of anti-tumor CD8+ T cells.[35] TREM2+ immunosuppressive TAMs correlate with the level of exhausted T cells in the human tumor microenvironment (TME).[36] A TREM2+ TAM-rich TME therefore appears to be immune suppressive and might promote resistance to cancer therapies, such as checkpoint inhibitors.

TREM2 signaling can antagonize TLR expression and signaling, resulting in reduced production of inflammatory cytokines by cultured mouse macrophages.[19] Conversely, TREM2 expression is reduced following inflammatory signaling induction by lipopolysaccharide (a TLR4 ligand) or interferon gamma (IFNG).[37] The neuroprotective effects of TREM2 involve not only production of anti-inflammatory cytokines, but also clearance of abnormal proteins and phagocytosis of apoptotic neurons.[14][34]

In contrast to anti-inflammatory effects in brain and cancer, TREM2 signaling has been reported to contribute to intestinal inflammation and development of inflammatory bowel diseases (IBD).[11] sTREM2 is believed to negatively regulate TREM2 signaling by acting as decoy receptors.[38] sTREM might therefore have pro-inflammatory effects.[19] sTREM2 has been indicated in activating signaling pathways such as PI3K and ERK through an unidentified receptor.[39] Levels of sTREM2 are increased in CSF of patients with Alzheimer's disease, and correlate with the CSF levels of disease biomarkers, such as t-tau and p-tau.[40]

Association with diseases

[edit]

TREM2 signaling has been associated with pathogenesis of several diseases. Variants of in the DAP12 (TYROBP) or TREM2 genes have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL or Nasu–Hakola disease).[41]

Mutations in TREM2 associated with Alzheimer's disease lead to decreased binding affinity for ligands, resulting in reduced microglial responses to amyloid-beta plaques. Created with BioRender.com

Alzheimer's disease

[edit]

Variants of TREM2 have been associated with neurodegenerative disorders, including Alzheimer's disease.[42] TREM2 is involved in the microglial response to the amyloid plaques that are characteristic of AD. Loss of TREM2 function reduces the responses of microglia to plaques, which then appear to take on a more toxic state.[42] Expression of TREM2 is associated with that of CD33.[43][44][45]

Zhong et al. reported that, in mice, stereotactic injection of sTREM2 or adeno-associated virus-mediated activation of sTREM2 reduced the amyloid plaque load and reduced functional memory deficits.[46] Moreover, sTREM2 stimulated microglial proliferation and homing toward amyloid plaques where amyloid-β uptake and degradation was increased. Interestingly, these effects were specifically mediated by microglia. Level of sTREM2 in the CSF might be a biomarker for Alzheimer's disease and the associated inflammatory response.[47][48][49]

Cancer

[edit]

Although TREM2 expression is low in most normal tissues, it is overexpressed in many human tumor types.[50] An analysis of levels of TREM2 mRNA in 33 cancer tissues from The Cancer Genome Atlas (TCGA) indicate higher levels of expression in tumor vs normal tissues in 18 cancer types, including head and neck squamous cell carcinoma, colon adenocarcinoma, and glioblastoma, as well as gynecologic, liver, gastric, kidney, breast, bladder, and esophageal cancers.[50] High expression of TREM2 was associated with shorter survival times of patients with ovarian cancer, gastric cancer, lower-grade glioma, hepatocellular carcinoma, or renal clear cell carcinoma.[50] Tumor infiltration by TREM2+, APOE+, C1q+ macrophage was reported to be a biomarker for recurrence of clear-cell renal carcinoma.[51][52] TREM2+ macrophages from human tumors also express CD68, CD163, CSF1R, and nuclear MAFB.[53]

IBD

[edit]

TREM2 expressed by human monocyte dendritic cells[11] in the intestine.[54] Expression of TREM2 is limited to inflamed sections of intestine and contribute to IBD development.[11] TREM2 is associated with increased production of inflammatory cytokines and changes in the gut microbiota.[11]

Liver disease

[edit]

One feature of liver disease is the initiation of an inflammatory process, leading to fibrosis and steatohepatitis. In mouse models of nonalcoholic steatohepatitis (NASH), disease development was associated with liver infiltration by monocyte-derived macrophages and increased expression of Trem2 and Cd9.[55] Mice with disruption of Trem2 had more severe liver damage following administration of carbon tetrachloride or acetaminophen, compared to mice without gene disruption.[56] The authors of this study found that TREM2 is expressed by Kupfer cells and hepatic stellate cells, indicating that TREM2 might downregulate inflammation.[56] Expression was also increased in liver tissues from patients with cirrhosis.[56] Compared with non-tumor liver tissue, TREM2 expression was increased in tumors from mice and patients with hepatocellular carcinoma (HCC).[57] This study also showed that disruption of Trem2 promoted tumor development and exacerbated liver damage and inflammation. In liver tumors, TREM2 was expressed by tumor-infiltrating macrophages (TAMs). TREM2 might therefore promote the resolution of inflammation during hepatic injury, ultimately preventing parenchymal cell death.

Mutations in the TREM2 or TYROBP genes (encodes DAP12) can lead to development of PLOSL. This disease is characterized by dysfunctional microglia, bone cysts and fractures, frontal lobe syndrome, and dementia. Created with BioRender.com

PLOSL or Nasu–Hakola disease

[edit]

PLOSL or Nasu–Hakola disease is a neurodegenerative disorder characterized by bone cysts, dementia, and early death and is associated with variants in the TYROBP gene (encodes DAP12 protein) and TREM2 gene.[41] Bone cysts in patients with PLOSL contain fat in lieu of bone marrow.[28] In this disease, the main cell type in the brain that is affected is the microglia, where TREM2 is expressed.[58] Several recessive, inactivating mutations in TREM2 and TYROBP (encodes DAP12 protein) have been identified that can cause PLOSL.[20][59][60] The mutations prevent association between TREM2 and DAP12 or expression of shorter, non-functional forms of TREM2.[28][60] Loss of function of TREM2 signaling increases the inflammatory responses of microglia,[58] reducing clearance of dead neurons and promoting inflammation and even formation of amyloid plaques.[58]

Stroke

[edit]

During ischemic stroke, microglia respond to the area of insult. TREM2 appears to reduce the inflammatory response induced by TLR signaling and promote microglial migration, survival, and regeneration.[61][62]

Other diseases

[edit]

TREM2 has also been linked to additional disorders such as ALS, Parkinson's disease, and more dementia related conditions.[20]

Therapeutic targeting of TREM2

[edit]

TREM2 is a good therapeutic target for several diseases, including cancer and liver and neurodegenerative diseases. Several companies are developing agents to target TREM2. However, TREM2 is likely to have distinct roles in the pathogenesis of these disorders, so therapeutic agents in development employ different approaches to modify TREM2 activity.

Neurodegenerative diseases

[edit]

In the brain, TREM2 is expressed on microglia that regulate clearance of neuronal debris.[19] Binding of apolipoproteins, such as ApoE, to TREM2 promotes phagocytosis of apoptotic neurons or the uptake of amyloid beta by microglia.[63] Variants of TREM2 that encode proteins with reduced affinity for ligands have been associated with Alzheimer’s disease.[64]

Targeting sTREM2

[edit]

A potential mechanism of intervention could be targeting the enzymes that cleave the ectodomain, adjusting the rate at which sTREM2 is released. In rodents, a potential therapeutic using this mechanism was used against AD pathology, and the rodents had smaller plaques than controls.[19]

References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000095970 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023992 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Bouchon A, Dietrich J, Colonna M (May 2000). "Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes". Journal of Immunology. 164 (10): 4991–4995. doi:10.4049/jimmunol.164.10.4991. PMID 10799849.
  6. ^ Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, et al. (September 2002). "Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype". American Journal of Human Genetics. 71 (3): 656–662. doi:10.1086/342259. PMC 379202. PMID 12080485.
  7. ^ "Entrez Gene: TREM2 triggering receptor expressed on myeloid cells 2".
  8. ^ Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MK, Herrera AJ, Espinosa-Oliva AM, et al. (July 2020). "Microglia: Agents of the CNS Pro-Inflammatory Response". Cells. 9 (7): E1717. doi:10.3390/cells9071717. PMC 7407646. PMID 32709045.
  9. ^ Masuda T, Sankowski R, Staszewski O, Prinz M (February 2020). "Microglia Heterogeneity in the Single-Cell Era". Cell Reports. 30 (5): 1271–1281. doi:10.1016/j.celrep.2020.01.010. PMID 32023447. S2CID 211047418.
  10. ^ Sun H, Feng J, Tang L (December 2020). "Function of TREM1 and TREM2 in Liver-Related Diseases". Cells. 9 (12): 2626. doi:10.3390/cells9122626. PMC 7762355. PMID 33297569.
  11. ^ a b c d e Genua M, Rutella S, Correale C, Danese S (October 2014). "The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis". Journal of Translational Medicine. 12: 293. doi:10.1186/s12967-014-0293-z. PMC 4231187. PMID 25347935.
  12. ^ a b c "TREM2 triggering receptor expressed on myeloid cells 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-11-02.
  13. ^ a b Natale G, Biagioni F, Busceti CL, Gambardella S, Limanaqi F, Fornai F (September 2019). "TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders". Cells. 8 (10): E1124. doi:10.3390/cells8101124. PMC 6829526. PMID 31546668.
  14. ^ a b c d e f Yang J, Fu Z, Zhang X, Xiong M, Meng L, Zhang Z (July 2020). "TREM2 ectodomain and its soluble form in Alzheimer's disease". Journal of Neuroinflammation. 17 (1): 204. doi:10.1186/s12974-020-01878-2. PMC 7341574. PMID 32635934.
  15. ^ "Jackson Laboratory Search- TREM2". Jackson Laboratory.
  16. ^ Smith JR, Hayman GT, Wang SJ, Laulederkind SJ, Hoffman MJ, Kaldunski ML, et al. (January 2020). "The Year of the Rat: The Rat Genome Database at 20: a multi-species knowledgebase and analysis platform". Nucleic Acids Research. 48 (D1): D731–D742. doi:10.1093/nar/gkz1041. PMC 7145519. PMID 31713623.
  17. ^ Kulkarni B, Kumar D, Cruz-Martins N, Sellamuthu S (October 2021). "Role of TREM2 in Alzheimer's Disease: A Long Road Ahead". Molecular Neurobiology. 58 (10): 5239–5252. doi:10.1007/s12035-021-02477-9. PMID 34275100. S2CID 236090999.
  18. ^ a b Hamerman JA, Pottle J, Ni M, He Y, Zhang ZY, Buckner JH (January 2016). "Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases". Immunological Reviews. 269 (1): 212–227. doi:10.1111/imr.12381. PMC 4703580. PMID 26683155.
  19. ^ a b c d e f g h i j k l Deczkowska A, Weiner A, Amit I (June 2020). "The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway". Cell. 181 (6): 1207–1217. doi:10.1016/j.cell.2020.05.003. PMID 32531244. S2CID 219572314.
  20. ^ a b c Dardiotis E, Siokas V, Pantazi E, Dardioti M, Rikos D, Xiromerisiou G, et al. (May 2017). "A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature". Neurobiology of Aging. 53: 194.e13–194.e22. doi:10.1016/j.neurobiolaging.2017.01.015. PMID 28214109. S2CID 22618858.
  21. ^ Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ (December 2016). "Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms". eLife. 5: e20391. doi:10.7554/eLife.20391. PMC 5173322. PMID 27995897.
  22. ^ De Kleer I, Willems F, Lambrecht B, Goriely S (2014). "Ontogeny of myeloid cells". Frontiers in Immunology. 5: 423. doi:10.3389/fimmu.2014.00423. PMC 4153297. PMID 25232355.
  23. ^ a b Futosi K, Fodor S, Mócsai A (November 2013). "Neutrophil cell surface receptors and their intracellular signal transduction pathways". International Immunopharmacology. 17 (3): 638–650. doi:10.1016/j.intimp.2013.06.034. PMC 3827506. PMID 23994464.
  24. ^ Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. (January 2018). "Inflammatory responses and inflammation-associated diseases in organs". Oncotarget. 9 (6): 7204–7218. doi:10.18632/oncotarget.23208. PMC 5805548. PMID 29467962.
  25. ^ Sancho D, Reis e Sousa C (February 2013). "Sensing of cell death by myeloid C-type lectin receptors". Current Opinion in Immunology. 25 (1): 46–52. doi:10.1016/j.coi.2012.12.007. PMC 4480265. PMID 23332826.
  26. ^ Kober DL, Brett TJ (June 2017). "TREM2-Ligand Interactions in Health and Disease". Journal of Molecular Biology. 429 (11): 1607–1629. doi:10.1016/j.jmb.2017.04.004. PMC 5485854. PMID 28432014.
  27. ^ Kober DL, Brett TJ (June 2017). "TREM2-Ligand Interactions in Health and Disease". Journal of Molecular Biology. 429 (11): 1607–1629. doi:10.1016/j.jmb.2017.04.004. PMC 5485854. PMID 28432014.
  28. ^ a b c d e Xing J, Titus AR, Humphrey MB (2015). "The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective". Research and Reports in Biochemistry. 5: 89–100. doi:10.2147/RRBC.S58057. PMC 4605443. PMID 26478868.
  29. ^ a b Qiu H, Shao Z, Wen X, Jiang J, Ma Q, Wang Y, et al. (2021). "TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy". Frontiers in Immunology. 12: 716710. doi:10.3389/fimmu.2021.716710. PMC 8446424. PMID 34539652.
  30. ^ a b Gratuze M, Leyns CE, Holtzman DM (December 2018). "New insights into the role of TREM2 in Alzheimer's disease". Molecular Neurodegeneration. 13 (1): 66. doi:10.1186/s13024-018-0298-9. PMC 6302500. PMID 30572908.
  31. ^ Hong S, Dissing-Olesen L, Stevens B (February 2016). "New insights on the role of microglia in synaptic pruning in health and disease". Current Opinion in Neurobiology. 36: 128–134. doi:10.1016/j.conb.2015.12.004. PMC 5479435. PMID 26745839.
  32. ^ Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, et al. (May 2018). "The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity". Immunity. 48 (5): 979–991.e8. doi:10.1016/j.immuni.2018.04.016. PMID 29752066. S2CID 21700781.
  33. ^ Molgora M, Colonna M (June 2021). "Turning enemies into allies-reprogramming tumor-associated macrophages for cancer therapy". Med. 2 (6): 666–681. doi:10.1016/j.medj.2021.05.001. PMC 8238417. PMID 34189494.
  34. ^ a b Takahashi K, Rochford CD, Neumann H (February 2005). "Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2". The Journal of Experimental Medicine. 201 (4): 647–657. doi:10.1084/jem.20041611. PMC 2213053. PMID 15728241.
  35. ^ Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, et al. (August 2020). "TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy". Cell. 182 (4): 886–900.e17. doi:10.1016/j.cell.2020.07.013. PMC 7485282. PMID 32783918.
  36. ^ Binnewies M, Pollack JL, Rudolph J, Dash S, Abushawish M, Lee T, et al. (October 2021). "Targeting TREM2 on tumor-associated macrophages enhances immunotherapy". Cell Reports. 37 (3): 109844. doi:10.1016/j.celrep.2021.109844. PMID 34686340. S2CID 239472808.
  37. ^ Gao X, Dong Y, Liu Z, Niu B (March 2013). "Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide". Molecular Medicine Reports. 7 (3): 921–926. doi:10.3892/mmr.2013.1268. PMID 23314916.
  38. ^ Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, et al. (November 2008). "Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation". Brain. 131 (Pt 11): 3081–3091. doi:10.1093/brain/awn217. PMC 2577803. PMID 18790823.
  39. ^ Konishi H, Kiyama H (2018). "Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases". Frontiers in Cellular Neuroscience. 12: 206. doi:10.3389/fncel.2018.00206. PMC 6087757. PMID 30127720.
  40. ^ Yang J, Fu Z, Zhang X, Xiong M, Meng L, Zhang Z (July 2020). "TREM2 ectodomain and its soluble form in Alzheimer's disease". Journal of Neuroinflammation. 17 (1): 204. doi:10.1186/s12974-020-01878-2. PMC 7341574. PMID 32635934.
  41. ^ a b Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, et al. (February 2004). "Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects". Cellular and Molecular Neurobiology. 24 (1): 1–24. doi:10.1023/b:cemn.0000012721.08168.ee. PMID 15049507. S2CID 7089775.
  42. ^ a b Shi Y, Holtzman DM (December 2018). "Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight". Nature Reviews. Immunology. 18 (12): 759–772. doi:10.1038/s41577-018-0051-1. PMC 6425488. PMID 30140051.
  43. ^ Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, et al. (September 2019). "TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease". Neuron. 103 (5): 820–835.e7. doi:10.1016/j.neuron.2019.06.010. PMC 6728215. PMID 31301936.
  44. ^ Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, et al. (November 2015). "CD33 modulates TREM2: convergence of Alzheimer loci". Nature Neuroscience. 18 (11): 1556–1558. doi:10.1038/nn.4126. PMC 4682915. PMID 26414614.
  45. ^ Stetka B (2022-01-30). "How a hyperactive cell in the brain might trigger Alzheimer's disease". NPR. Retrieved 2022-02-17.
  46. ^ Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, et al. (March 2019). "Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model". Nature Communications. 10 (1): 1365. Bibcode:2019NatCo..10.1365Z. doi:10.1038/s41467-019-09118-9. PMC 6433910. PMID 30911003.
  47. ^ Liu D, Cao B, Zhao Y, Huang H, McIntyre RS, Rosenblat JD, Zhou H (November 2018). "Soluble TREM2 changes during the clinical course of Alzheimer's disease: A meta-analysis". Neuroscience Letters. 686: 10–16. doi:10.1016/j.neulet.2018.08.038. PMID 30171911. S2CID 52146124.
  48. ^ Rauchmann BS, Schneider-Axmann T, Alexopoulos P, Perneczky R (February 2019). "CSF soluble TREM2 as a measure of immune response along the Alzheimer's disease continuum". Neurobiology of Aging. 74: 182–190. doi:10.1016/j.neurobiolaging.2018.10.022. PMC 6331262. PMID 30458365.
  49. ^ Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, et al. (June 2016). "Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status". Acta Neuropathologica. 131 (6): 925–933. doi:10.1007/s00401-016-1533-5. PMC 4867123. PMID 26754641.
  50. ^ a b c Cheng X, Wang X, Nie K, Cheng L, Zhang Z, Hu Y, Peng W (2021). "Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker". Frontiers in Immunology. 12: 646523. doi:10.3389/fimmu.2021.646523. PMC 7925850. PMID 33679809.
  51. ^ Binnewies M, Pollack JL, Rudolph J, Dash S, Abushawish M, Lee T, et al. (October 2021). "Targeting TREM2 on tumor-associated macrophages enhances immunotherapy". Cell Reports. 37 (3): 109844. doi:10.1016/j.celrep.2021.109844. PMID 34686340. S2CID 239472808.
  52. ^ Obradovic A, Chowdhury N, Haake SM, Ager C, Wang V, Vlahos L, et al. (May 2021). "Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages". Cell. 184 (11): 2988–3005.e16. doi:10.1016/j.cell.2021.04.038. PMC 8479759. PMID 34019793.
  53. ^ Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, et al. (August 2020). "TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy". Cell. 182 (4): 886–900.e17. doi:10.1016/j.cell.2020.07.013. PMC 7485282. PMID 32783918.
  54. ^ Stagg AJ (2018). "Intestinal Dendritic Cells in Health and Gut Inflammation". Frontiers in Immunology. 9: 2883. doi:10.3389/fimmu.2018.02883. PMC 6291504. PMID 30574151.
  55. ^ Coelho I, Duarte N, Macedo MP, Penha-Gonçalves C (March 2021). "Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2". Journal of Clinical Medicine. 10 (6): 1248. doi:10.3390/jcm10061248. PMC 8002813. PMID 33802948.
  56. ^ a b c Perugorria MJ, Esparza-Baquer A, Oakley F, Labiano I, Korosec A, Jais A, et al. (March 2019). "Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage". Gut. 68 (3): 533–546. doi:10.1136/gutjnl-2017-314107. PMC 6580759. PMID 29374630.
  57. ^ Esparza-Baquer A, Labiano I, Sharif O, Agirre-Lizaso A, Oakley F, Rodrigues PM, et al. (July 2021). "TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms". Gut. 70 (7): 1345–1361. doi:10.1136/gutjnl-2019-319227. PMC 8223629. PMID 32907830.
  58. ^ a b c Mecca C, Giambanco I, Donato R, Arcuri C (January 2018). "Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes". International Journal of Molecular Sciences. 19 (1): E318. doi:10.3390/ijms19010318. PMC 5796261. PMID 29361745.
  59. ^ Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, et al. (July 2000). "Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts". Nature Genetics. 25 (3): 357–361. doi:10.1038/77153. PMID 10888890. S2CID 9243117.
  60. ^ a b Walter J (February 2016). "The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases". The Journal of Biological Chemistry. 291 (9): 4334–4341. doi:10.1074/jbc.R115.704981. PMC 4813462. PMID 26694609.
  61. ^ Gervois P, Lambrichts I (2019). "The Emerging Role of Triggering Receptor Expressed on Myeloid Cells 2 as a Target for Immunomodulation in Ischemic Stroke". Frontiers in Immunology. 10: 1668. doi:10.3389/fimmu.2019.01668. PMC 6650572. PMID 31379859.
  62. ^ Ulrich JD, Holtzman DM (April 2016). "TREM2 Function in Alzheimer's Disease and Neurodegeneration". ACS Chemical Neuroscience. 7 (4): 420–427. doi:10.1021/acschemneuro.5b00313. PMID 26854967.
  63. ^ Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, et al. (October 2015). "Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)". The Journal of Biological Chemistry. 290 (43): 26043–26050. doi:10.1074/jbc.M115.679043. PMC 4646257. PMID 26374899.
  64. ^ Guerreiro R, Hardy J (October 2013). "TREM2 and neurodegenerative disease". The New England Journal of Medicine. 369 (16): 1569–1570. doi:10.1056/NEJMc1306509. PMC 3980568. PMID 24143816.
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