Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015-2020 updates

References

• Ford JW, McVicar DW. TREM and TREM-like receptors in inflammation and disease. Current Opinion in Immunology. 2009;21(1):38–46.
   PubMed Web of Science ®Google Scholar
• Radaev S, Kattah M, Rostro B, et al. Crystal Structure of the Human Myeloid Cell Activating Receptor TREM-1. Structure. 2003;11(12):1527–1535. .
   PubMed Web of Science ®Google Scholar
• Lanier LL, Corliss BC, Wu J, et al. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature. 1998;391(6668):703–707. .
   PubMed Web of Science ®Google Scholar
• Kelker MS, Foss TR, Peti W, et al. Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 147Å. J Mol Biol. 2004b;342:1237–1248.
   PubMed Web of Science ®Google Scholar
• Allcock RJN, Barrow AD, Forbes S, et al. The human TREM gene cluster at 6p21.1. encodes both activating and inhibitory single IgV domain receptors and includes NKp44. Eur J Immunol. 2003;33:567–577.
   PubMed Web of Science ®Google Scholar
• Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164:4991–4995.
   PubMed Web of Science ®Google Scholar
• Bouchon A, Facchetti F, Weigand MA, et al. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410:1103–1107.
   PubMed Web of Science ®Google Scholar
• Colonna M, Facchetti FTREM. 1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. J Infect Dis. 2003;187:S397–S401.
   PubMed Web of Science ®Google Scholar
• Sharif O, Knapp S. From expression to signaling: roles of TREM-1 and TREM-2 in innate immunity and bacterial infection. Immunobiology. 2008;213:701–713.
   PubMed Web of Science ®Google Scholar
• Chen LC, Laskin JD, Gordon MK, et al. Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia. Exp Mol Pathol. 2008;84:145–155.
   PubMed Web of Science ®Google Scholar
• Rigo I, McMahon L, Dhawan P, et al. Induction of triggering receptor expressed on myeloid cells (TREM-1) in airway epithelial cells by 1,25(OH)(2) vitamin D(3). Innate Immun. 2012;18:250–257.
   PubMed Web of Science ®Google Scholar
• Joffre J, Hau E, Zeboudj L, et al. Trem-1 is not crucial in psoriasiform imiquimod-induced skin inflammation in mice. Exp Dermatol. 2016a;25:400–402.
   PubMed Web of Science ®Google Scholar
• Joffre J, Potteaux S, Zeboudj L, et al. Genetic and pharmacological inhibition of TREM-1 limits the development of experimental atherosclerosis. J Am Coll Cardiol. 2016b;68:2776–2793.
   PubMed Web of Science ®Google Scholar
• Zysset D, Weber B, Rihs S, et al. TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis. Nat Commun. 2016;7:13151.
   PubMed Web of Science ®Google Scholar
• Boufenzer A, Lemarie J, Simon T, et al. TREM-1 mediates inflammatory injury and cardiac remodeling following myocardial infarction. Circ Res. 2015;116:1772–1782.
   PubMed Web of Science ®Google Scholar
• Liu M, Wu W, Zhao Q, et al. High expression levels of trigger receptor expressed on myeloid cells-1 on neutrophils associated with increased severity of acute pancreatitis in mice. Biol Pharm Bull. 2015;38:1450–1457.
   PubMed Web of Science ®Google Scholar
• Lee J, Lee SY, Lee J, et al. Monosodium urate crystal-induced triggering receptor expressed on myeloid cells 1 is associated with acute gouty inflammation. Rheumatology (Oxford). 2016;55:156–161.
   PubMed Web of Science ®Google Scholar
• Tammaro A, Kers J, Emal D, et al. Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation. Sci Rep. 2016;6:38275.
   PubMed Web of Science ®Google Scholar
• Joffre J, Hau E, Zeboudj L, et al. Trem-1 is not crucial in psoriasis form imiquimod-induced skin inflammation in mice. Exp Dermatol. 2016;25:400–402.
   PubMed Web of Science ®Google Scholar
• Matesanz-Isabel J, Sintes J, Llinas L, et al. New B-cell CD molecules. Immunol Lett. 2011;134:104–112.
   PubMed Web of Science ®Google Scholar
• Rigo I, McMahon L, Dhawan P, et al. Induction of triggering receptor expressed on myeloid cells (TREM-1) in airway epithelial cells by 1,25(OH)2 vitamin D3. Innate Immun. 2011;18:250–257.
   PubMed Web of Science ®Google Scholar
• Klesney-Tait J, Turnbull IR, The CM. TREM receptor family and signal integration. Nat Immunol. 2006;7:1266–1273.
   PubMed Web of Science ®Google Scholar
• Gomez-Pina V, Soares-Schanoski A, Rodríguez-Rojas A, et al. Metalloproteinases shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes. J Immunol. 2007;179:4065–4073.
   PubMed Web of Science ®Google Scholar
• Gingras M-C, Lapillonne H, Margolin JF. TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development. Mol Immunol. 2002;38::817–824.
   PubMed Web of Science ®Google Scholar
• Gibot S, Cravoisy A, Levy B, et al. Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia. N Engl J Med. 2004;350:451–458.
   PubMed Web of Science ®Google Scholar
• Gibot S, Kolopp-sarda M, Rene MC, et al. Plasma level of a triggering receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with suspected sepsis. Ann Inter Med. 2004;141:9–15.
   PubMed Web of Science ®Google Scholar
• Barraud D, Gibot S. Triggering receptor expressed on myeloid cell 1. Crit Care Clin. 2011;27:265–279.
   PubMed Web of Science ®Google Scholar
• Kluckova K, Kozak J, Szaboova K, et al. TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients. Mediators Inflammation. 2020;2020:1798147.
   PubMed Web of Science ®Google Scholar
• Determann RM, Weisfelt M, deGans J, et al. Soluble triggering receptor expressed on myeloid cells 1: a biomarker for bacterial meningitis. Intensive Care Med. 2006;32:1243–1247.
   PubMed Web of Science ®Google Scholar
• Bishara J, Hadari N, Shalita-Chesner M, et al. Soluble triggering receptor expressed on myeloid cells-1 for distinguishing bacterial from aseptic meningitis in adults. Eur J Clin Microbiol Infect Dis. 2007;26:647–650.
   PubMed Web of Science ®Google Scholar
• Nguyen AH, Lim VM, Fleegel JP, et al. Cutaneous expression of TREM, vitamin D receptor and HMGB1 in vitamin D deficiency. Int J Clin Exp Pathol. 2016;9(8):8506–8512.
   PubMed Web of Science ®Google Scholar
• Rao VH, Rai V, Stoupa S, et al. Tumor Necrosis Factor-a Regulates Triggering Receptor Expressed on Myeloid Cells-1-dependent Matrix Metalloproteinases in the Carotid Plaques of Symptomatic Patients with Carotid Stenosis. Atherosclerosis. 2016;248:160–169.
   PubMed Web of Science ®Google Scholar
• Subramanian S, Pallati PK, Sharma P, et al. Significant association of TREM-1 with HMGB1, TLRs and RAGE in the pathogenesis of insulin resistance in obese diabetic populations. Am J Transl Res. 2017;9:3224–3244.
   PubMed Web of Science ®Google Scholar
• Tessarz AS, The CA. TREM-1/DAP12 pathway. Immunol Lett. 2008;116:111–116.
   PubMed Web of Science ®Google Scholar
• Lemarie J, Boufenzer A, Popovic B, et al. Pharmacological inhibition of the triggering receptor expressed on myeloid cells-1 limits reperfusion injury in a porcine model of myocardial infarction. ESC Heart Fail. 2015;2:90–99.
   PubMed Web of Science ®Google Scholar
• Dower K, Ellis DK, Saraf K, et al. Innate immune responses to TREM-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide. J Immunol. 2008;180:3520–3534.
   PubMed Web of Science ®Google Scholar
• Arts RJW, Joosten LAB, JWM V, et al. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukocyte Biol. 2013;93:209–215.
   PubMed Web of Science ®Google Scholar
• Haselmayer P, Grosse-Hovest L, vonLandenberg P, et al. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood. 2007;110:1029–1035.
   PubMed Web of Science ®Google Scholar
• Kevin C, Amir B, Lucie J, et al. TREM-1 multimerization is essential for its activation on monocytes and neutrophils. Cell Mol Immunol. 2019;5:460–472.
   Google Scholar
• Mariani M, Sinigaglia F, Panina P Diagnostic and prognostic compounds and method. US20060183125A1.
   Google Scholar
• Wong-Baeza I, Gonzalez-Roldan N, Ferat-Osorio E, et al. Triggering receptor expressed on myeloid cells (TREM-1) is regulated post-transcriptionally and its ligand is present in the sera of some septic patients. Clin Exp Immunol. 2006;145:448–455.
   PubMed Web of Science ®Google Scholar
• Gibot S, Buonsanti C, Massin F, et al. Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock. Infect Immun. 2006;74:2823–2830.
   PubMed Web of Science ®Google Scholar
• Cioni B, Zaalberg A, Beijnum JRV, et al. Androgen receptor signaling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nat Commun. 2020;11:4498.
   PubMed Web of Science ®Google Scholar
• Dantas PHS, Matos AO, Filho ES, et al. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol. 2020;39:188–202.
   PubMed Web of Science ®Google Scholar
• University HP Method of diagnosing infectious disease by measuring the level of soluble TREM-1 in a sample. 2007 US20070281319A1.
   Google Scholar
• Clinicaltrials.gov NCT03463044. Safety, Tolerability and Pharmacokinetic Profiles of MOTREM (LR12) in Healthy Male Subjects. Available from: https://clinicaltrials.gov/ct2/show/NCT03463044?term=NCT03463044&draw=2&rank=1 ( Retrieved on 2020 Oct 10)
   Google Scholar
• Clinicaltrials.gov NCT03158948. Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients With Septic Shock. Available from: https://clinicaltrials.gov/ct2/show/NCT03158948?term=NCT03158948&draw=2&rank=1. ( Retrieved on 2020 Oct 10)
   Google Scholar
• Derive M, Bouazza Y, Sennoun N, et al. Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis. J Immunol. 2012;188:5585–5592.
   PubMed Web of Science ®Google Scholar
• Weber B, Schuster S, Zysset D, et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathog. 2014;10:e1003900.
   PubMed Web of Science ®Google Scholar
• Derive M, Massin F, Gibot S. Effects of a TREM-like Transcript-1-derived peptide during hypodynamic shock in pigs. Shock. 2013;39:176–182.
   PubMed Web of Science ®Google Scholar
• Derive M, Boufenzer A, Gibot S. Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate. Anesthesiology. 2014;120:42–9350.
   PubMed Web of Science ®Google Scholar
• Sigalov AB. A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock. Int Immunopharmacol. 2014;21:208–219.
   PubMed Web of Science ®Google Scholar
• Amatngalim GD, Nijnik A, Hiemstra AN, et al. Cathelicidin Peptide LL-37 Modulates TREM-1 Expression and Inflammatory Responses to Microbial Compounds. Inflammation. 2011;34:412–425.
   PubMed Web of Science ®Google Scholar
• Lalezari P, Murphy GB, Jr Allen FH. NB1, a new neutrophil specific antigen involved in the pathogenesis of neonatal neutropenia. J Clin Invest. 1971;50:1108–1115.
   PubMed Web of Science ®Google Scholar
• Colonna M, Klesney-Tait J, Panina P Screening, therapy and diagnosis. US20100306863A1. 2010.
   Google Scholar
• Fu L, Han L, Xie C, et al. Identification of extracellular actin as a ligand for triggering receptor expressed on myeloid cells 1, signaling. Front Immunol. 2017;8:917.
   PubMed Web of Science ®Google Scholar
• Mohamadzadeh M, Coberley SS, Olinger GG, et al. Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by Marburg and Ebola viruses. J Virol. 2006;80:7235–7244.
   PubMed Web of Science ®Google Scholar
• Read CB, Kuijper JL, Hjorth SA. Cutting edge: identification of Neutrophil PGLYRP1as a Ligand of TREM-1. J Immunol. 2015;194:1417–1421.
   PubMed Web of Science ®Google Scholar
• Saha S, Jing X, Park S, et al. Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma. Cell Host Microbe. 2010;8:147–162.
   PubMed Web of Science ®Google Scholar
• Zulfiqar F, Hozo I, Rangarajan S, et al. Genetic association of peptidoglycan recognition protein variants with inflammatory bowel disease. PLoS One. 2013;8:e67393.
   PubMed Web of Science ®Google Scholar
• Stennicke VW, Read CB, Grell SN, et al. Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1). US20150274825A1.
   Google Scholar
• Novo Nordisk: assignee. Site directed mutagenesis of TREM-1 antibodies for decreasing viscosity. EP2975056A1.
   Google Scholar
• Wu B, Brooks JD. Gene expression changes induced by unilateral ureteral obstruction in mice. J Urol. 2012;188:1033–1041.
   PubMed Web of Science ®Google Scholar
• Lo TH, Tseng KY, Tsao WS, et al. TREM-1 regulates macrophage polarization in ureteral obstruction. Kidney Int. 2014;86:1174–1186.
   PubMed Web of Science ®Google Scholar
• Mezayen RE, Gazzar ME, Seeds MC, et al. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007;111:36–44.
   PubMed Web of Science ®Google Scholar
• Wu J, Salcedo JL. Mivechi, NF et al. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. 2012;72::3977–3986.
   PubMed Web of Science ®Google Scholar
• Gibot S, Massin F, Alauzet C, et al. Effects of the TREM 1 pathway modulation during hemorrhagic shock in rats, Targeting HMGB1 in inflammation. Shock. 2009;32:633–637.
   PubMed Web of Science ®Google Scholar
• Saurer L, Zysset D, Rihs S, et al. TREM-1 inhibition attenuates inflammation and tumor within the colon. Sci Rep. 2017;7:14870.
   PubMedGoogle Scholar
• Gibot S, Massin F, Alauzet C, et al. Effects of the TREM-1 pathway modulation during mesenteric ischemia-reperfusion in rats. Crit Care Med. 2008;36:504–510.
   PubMed Web of Science ®Google Scholar
• Murakami Y, Akahoshi T, Aoki N, et al. Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis. Arthritis Rheum. 2009;60:1615–1623.
   PubMed Web of Science ®Google Scholar
• Denninger KCM, Litman T, Marstrand T, et al. Kinetics of gene expression and bone remodeling in the clinical phase of collagen-induced arthritis. Arthritis Res Ther. 2015;17:43.
   PubMed Web of Science ®Google Scholar
• Dang S, Shen Y, Yin K, et al. TREM-1 promotes pancreatitis-associated intestinal barrier dysfunction. Gastroenterol Res Pract. 2012;2012:720865.
   PubMed Web of Science ®Google Scholar
• Qiang X, Yang WL, Wu R, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19:1489–1495.
   PubMed Web of Science ®Google Scholar
• Yang WL, Sharma A, Wang Z, et al. Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Sci Rep. 2016;6:26571.
   PubMed Web of Science ®Google Scholar
• Ode Y, Aziz M, Wang P. CIRP increases ICAM-1+ phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis. J Leukocyte Biol. 2018;103:693–707.
   PubMed Web of Science ®Google Scholar
• Aziz M, Brenner M, Wang P. Extracellular CIRP (eCIRP) and inflammation. J Leukocyte Biol. 2019;106:133–146.
   PubMed Web of Science ®Google Scholar
• Denning NL, Aziz M, Murao A, et al. Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight. 2020;5:e134172.
   PubMed Web of Science ®Google Scholar
• James ML, Andreasson KI Labeled probe and methods of use. WO2017083682A1; [cited 2021 Jan 16] https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017083682
   Google Scholar
• Arts RJ, Joosten LA, Dinarello CA, et al. TREM-1 interaction with the LPS/TLR4 receptor complex. 2011;22:11–14. European Cytokine Netw.
   PubMed Web of Science ®Google Scholar
• Cheng PC, Lin CN, Chen YJ, et al. Triggering receptor expressed on myeloid cells (TREM)-1 participates in Schistosoma mansoni inflammatory responses. Parasite Immunol. 2011;33:276–286.
   PubMed Web of Science ®Google Scholar
• Denner J, Eschricht M, Lauck M, et al. Modulation of cytokine release and gene expression by the immunosuppressive domain of gp41 of HIV-1. PLoS One. 2013;8:e55199.
   PubMed Web of Science ®Google Scholar
• Morozov VA, Morozov AV, Semaan M, et al. Single mutations in the transmembrane envelope protein abrogate the immunosuppressive property of HIV-1. Retrovirology. 2012;9:67.
   PubMed Web of Science ®Google Scholar
• Hyun J, McMahon RS, Lang AL, et al. HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells. PLoS Pathog. 2019;15:e1007883.
   PubMed Web of Science ®Google Scholar
• Nochi H, Aoki N, Oikawa K, et al. Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules. Am J Pathol. 2003;162:1191–1201.
   PubMed Web of Science ®Google Scholar
• Sigalov AB. Immune cell signaling: a novel mechanistic model reveals new therapeutic targets. Trends Pharmacol Sci. 2006;27:518–524.
   PubMed Web of Science ®Google Scholar
• Signablok Inc SA, assignee. Inhibition of TREM receptor signaling with peptide variants. US Patent 20120202733A1; HYPERLINK https://patents.google.com/patent/US20120202733A1/en.
   Google Scholar
• Pelham CJ, Pandya AN, Agrawal DK. Triggering receptor expressed on myeloid cells (TREM) receptor family modulators: a patent review. Expert Opin Ther Pat. 2014;24:1383–1395.
   PubMed Web of Science ®Google Scholar
• Shen ZT, Sigalov AB. Rationally designed ligand-independent peptide inhibitors of TREM-1 ameliorate collagen-induced arthritis. J Cell Mol Med. 2017;21:2524–2534.
   PubMed Web of Science ®Google Scholar
• Shen ZT, Sigalov AB. Novel TREM-1 Inhibitors Attenuate Tumor Growth and Prolong Survival in Experimental Pancreatic Cancer. Mol Pharm. 2017;14:4572–4582.
   PubMedGoogle Scholar
• Rojas MA, Shen ZT, Caldwell RB, et al. Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy. Biochim Biophys Acta Mol Basis Dis. 2018;1864:2761–2768.
   PubMed Web of Science ®Google Scholar
• Tornai D, Furi I, Shen ZT, et al. Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice. Hepatol Commun. 2019;3:99–115.
   PubMed Web of Science ®Google Scholar
• Wu Q, Zhou W, Yin S, et al. 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. Hepatology. 2019;70:198–214.
   PubMed Web of Science ®Google Scholar
• Wang HM, Gao JH, Lu JL. Pravastatin improves atherosclerosis in mice with hyperlipidemia by inhibiting TREM-1/DAP12. Eur Rev Med Pharmacol Sci. 2018;22:4995–5003.
   PubMed Web of Science ®Google Scholar
• Schmid CD, Sautkulis LN, Danielson PE, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002;83:1309–1320.
   PubMed Web of Science ®Google Scholar
• Han X, Zhou Z, Fei L, et al. Construction of a human cell landscape at single-cell level. Nature. 2020;581:303–309.
   PubMed Web of Science ®Google Scholar
• Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell. 2019;178:686–698.
   PubMed Web of Science ®Google Scholar
• Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17:201–207.
   PubMed Web of Science ®Google Scholar
• Hall SC, Agrawal DK. Increased TREM-2 expression on the subsets of CD11c+ cells in the lungs and lymph nodes during allergic airway inflammation. Sci Rep. 11853;2017:7.
   PubMed Web of Science ®Google Scholar
• Kober DL, Brett TJ. TREM2-ligand interactions in health and disease. J Mol Biol. 2017;429:1607–1629.
   PubMed Web of Science ®Google Scholar
• Zhang J, Liu Y, Zheng Y, et al. TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus. J Neuroinflammation. 2020;17:2.
   PubMed Web of Science ®Google Scholar
• Chen QX, Yang Y, Wu XL, et al. Triggering Receptor Expressed On Myeloid Cells-2 Protects Aged Mice Against Sepsis By Mitigating The IL-23/IL-17A Response. Shock. 2020. DOI:10.1097/SHK.0000000000001668.
   Google Scholar
• Esparza-Baquer A, Labiano I, Sharif O, et al. TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms. Gut. 2020;319227:1–17.
   Google Scholar
• Peng Q, Malhotra S, Torchia JA, et al. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal. 2010;3:ra38.
   PubMed Web of Science ®Google Scholar
• Zhong L, Wang Z, Wang D, et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol Neurodegener. 2018;13:15.
   PubMed Web of Science ®Google Scholar
• Wang Y, Cella M, Mallinson K, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015;160:1061–1071.
   PubMed Web of Science ®Google Scholar
• Yeh FL, Wang Y, Tom I, et al. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron. 2016;91:328–340.
   PubMed Web of Science ®Google Scholar
• Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169:1276–1290.
   PubMed Web of Science ®Google Scholar
• Parhizkar S, Arzberger T, Brendel M, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22:191–204.
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov NCT03635047. A Phase I Study for Safety and Tolerability of AL002. Available from https://clinicaltrials.gov/ct2/show/NCT03635047?term=NCT03635047&draw=2&rank=1 ( Retrieved on 2020 Oct 10).
   Google Scholar
• Wang A, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med. 2020;21:e20200785.
   Google Scholar
• Voytyuk I, De Strooper B, Chavez-Gutierrez L. Modulation of gand b-Secretases as Early Prevention Against Alzheimer’s Disease. Biol Psychiatry. 2018;83:320–327.
   PubMed Web of Science ®Google Scholar
• Schlepckow K, Kleinberger G, Fukumori A, et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med. 2017;9:1356–1365.
   PubMed Web of Science ®Google Scholar
• Schlepckow K, Monroe KM, Kleinberger G, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020;12:e11227.
   PubMed Web of Science ®Google Scholar
• Kang KW, Kim N, Yoon KR Pharmaceutical composition, comprising gold compound, for preventing or treating liver fibrosis or liver cirrhosis. EP3184113A2.
   Google Scholar
• Abdel-Rafei M, Thabet NM. Modulatory effect of methylsulfonylmethane against BPA/?-radiation induced neurodegenerative alterations in rats: influence of TREM-2/DAP-12/Syk pathway. Life Sci. 2020;260:118410.
   PubMed Web of Science ®Google Scholar
• Haass C, Kleinberger G, Schlepckow K TREM2 cleavage modulators and uses thereof. WO2018015573A2.
   Google Scholar
• Brand V, Feuerbach D, Gasparini F, et al. TREM2 stabilizing antibodies. WO20200079580A1.
   Google Scholar
• Foltz I, Sambashivan S, Chen I, et al. TREM2 antigen binding proteins and uses thereof. WO2018195506A1.
   Google Scholar
• Holtzman D, Ulrich J, Jiang H Anti-TREM-2 agonist antibodies. WO2020055975A1.
   Google Scholar
• Fassler M, George J TREM2 antibodies and uses thereof. WO2020121195A1.
   Google Scholar
• Streuli M, Sriram V, Pal A, et al. Anti-TREM-2 antibodies and related methods. WO2019118513A1.
   Google Scholar
• Ellwanger DC, Wang S, Brioschi S, et al. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease. PNAS. 2021;118:e2017742118.
   PubMed Web of Science ®Google Scholar
• Fassler M, Rappaport MS, Benaim C, et al. Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models. J Neuroinflammation. 2021;18:19.
   PubMed Web of Science ®Google Scholar
• Dennis M, Duncan S, Lisaingo K, et al. Anti-TREM2 antibodies and methods of use thereof. WO2020172457A1.
   Google Scholar
• Tina S, Eric B, Philip K, et al. Anti-TREM2 antibodies and methods of use thereof. US2020317776A1.
   Google Scholar
• Chung DH, Seaman WE, Daws MR. Characterization of TREM-3, an activating receptor on mouse macrophages: definition of a family of single ig domain receptors on mouse chromosome 17. Eur J Immunol. 2002;32:59–66.
   PubMed Web of Science ®Google Scholar
• Colonna M, Bioxell SpA PP. assignee. Novel receptor TREM (triggering receptor expressed on myeloid cells) and uses thereof. US20060263770A1.
   Google Scholar
• Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of alzheimer’s disease. N Engl J Med. 2013;368:107–116.
   PubMed Web of Science ®Google Scholar