The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Alzheimer’s disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling. Alzheimer’s disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling. In recent years, the research community has turned its attention toward the central role of myeloid cells in diverse pathologies, with triggering receptor expressed on myeloid cells-2 (TREM2) highlighted as a major pathology-induced immune signaling hub. TREM2 is a receptor interacting with a wide array of ligands, many of which occur as hallmarks of tissue damage. In physiology, TREM2 activity is restricted to a small number of niches, but in pathology, the TREM2 pathway becomes central for sensing tissue damage and restricting its spread. These discoveries have inspired diverse programs in academia and industry exploring the exciting possibility of therapeutic TREM2 manipulation. On the other hand, to date, various aspects of TREM2 signaling, from the molecular level of receptor-ligand interaction and signaling to control of the tissue microenvironment, remain poorly understood. The goal of this perspective is to summarize the current knowledge and outline important avenues of future research regarding TREM2 signaling and its role in pathology. We first review the molecular machinery of TREM2 signaling and dissect consequences of its activation at a cellular level. A major focus is on processes that can modulate the outcome of TREM2 activation in vivo: the wide array of TREM2 ligands and other pathways that synergize or compete with TREM2 signaling. We describe the roles of TREM2 in physiology and discuss how its activation affects cellular phenotypes through modulation of phagocytosis and metabolism, promoting cell survival and counteracting inflammation. Finally, we turn to the roles of TREM2 in pathology and the possible therapeutic approaches to TREM2 manipulation in the clinic, focusing on Alzheimer’s disease, metabolic syndrome, and cancer. TREM2 is a transmembrane receptor of the immunoglobulin superfamily (Figure 1A). The ligands of TREM2 encompass a wide array of anionic molecules, free and bound to the plasma membrane, including bacterial products, DNA, lipoproteins, and phospholipids (thoroughly reviewed in Kober and Brett, 2017Kober D.L. Brett T.J. TREM2-Ligand Interactions in Health and Disease.J. Mol. Biol. 2017; 429: 1607-1629Crossref PubMed Scopus (62) Google Scholar). TREM2 consists of an extracellular domain that includes a single V-type immunoglobulin domain, a short ectodomain, a single transmembrane helix, and a short cytosolic tail that lacks any signal transduction or trafficking motifs. Instead, studies on mouse macrophages showed that TREM2 associates with the adaptor proteins DNAX activation protein 12 (DAP12) and DAP10 via oppositely charged residues in their transmembrane domains. Upon TREM2-ligand interaction, these co-receptors are phosphorylated and recruit intracellular signal transduction machinery. DAP12, also known as TYRO protein tyrosine kinase-binding protein (TYROBP), mediates activation of spleen tyrosine kinase Syk, whereas DAP10 promotes signal propagation by recruiting phosphatidylinositol 3-kinase (PI3K). TREM2 can bind DAP12 or DAP10 and possibly form TREM2-DAP12-DAP10 heterodimers (Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar). Downstream signaling is critically dependent on these arrangements; for example, in mouse macrophages, DAP12 is required for Ca2+ mobilization, whereas DAP10 is critical for activation of serine/threonine protein kinase (AKT1) and extracellular signal-regulated kinase (ERK) (Otero et al., 2012Otero K. Shinohara M. Zhao H. Cella M. Gilfillan S. Colucci A. Faccio R. Ross F.P. Teitelbaum S.L. Takayanagi H. Colonna M. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.J. Immunol. 2012; 188: 2612-2621Crossref PubMed Scopus (87) Google Scholar, Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar, Ulland et al., 2017Ulland T.K. Song W.M. Huang S.C.-C. Ulrich J.D. Sergushichev A. Beatty W.L. Loboda A.A. Zhou Y. Cairns N.J. Kambal A. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease.Cell. 2017; 170: 649-663.e13Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar). Our current knowledge about the TREM2 signaling pathway is nevertheless based on simplified biochemical assays and in vitro cultures (Cella et al., 2003Cella M. Buonsanti C. Strader C. Kondo T. Salmaggi A. Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals.J. Exp. Med. 2003; 198: 645-651Crossref PubMed Scopus (169) Google Scholar, Otero et al., 2012Otero K. Shinohara M. Zhao H. Cella M. Gilfillan S. Colucci A. Faccio R. Ross F.P. Teitelbaum S.L. Takayanagi H. Colonna M. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.J. Immunol. 2012; 188: 2612-2621Crossref PubMed Scopus (87) Google Scholar, Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar; Figure 1A). The in vivo picture of TREM2 signaling is expected to have much higher complexity. First, TREM2 was suggested to bind a large number of molecules (Kober and Brett, 2017Kober D.L. Brett T.J. TREM2-Ligand Interactions in Health and Disease.J. Mol. Biol. 2017; 429: 1607-1629Crossref PubMed Scopus (62) Google Scholar), and interaction with different ligands can differentially modulate TREM2 signaling strength and direction (Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar). Although, in mice and humans, the immune receptor tyrosine-based activation motif (ITAM) of DAP12 is considered activating, studies in mice have proposed that low-affinity/avidity ligands can promote partial DAP12 phosphorylation and consequent recruitment of the SH2 domain-containing protein tyrosine phosphatase SHP-1, which then dephosphorylates downstream targets of Syk kinase, inhibiting cellular activation (Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar). In addition, the wide range of TREM2 ligands significantly complicates predictions regarding the effects of their binding. Some ligands are physiologically present in the body; for example, lipoproteins (low-density lipoprotein [LDL]) and apolipoproteins (APOE), possibly inducing a tonic TREM2 signal. An additional cocktail of ligands is released as a consequence of tissue damage and cell death. For example, in the case of bacterial infection, where tissue damage and pathogen invasion co-occur, TREM2 binds bacterial anionic molecules, such as lipopolysaccharide (LPS) and dextran sulfates, as well as cell debris via various surface phospholipids (phosphatidylserine, cardiolipin, etc.) and glycolipids (sulfatides, other cerebrosides, etc.) (Hsieh et al., 2009Hsieh C.L. Koike M. Spusta S.C. Niemi E.C. Yenari M. Nakamura M.C. Seaman W.E. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia.J. Neurochem. 2009; 109: 1144-1156Crossref PubMed Scopus (259) Google Scholar, Kober and Brett, 2017Kober D.L. Brett T.J. TREM2-Ligand Interactions in Health and Disease.J. Mol. Biol. 2017; 429: 1607-1629Crossref PubMed Scopus (62) Google Scholar). In Alzheimer’s disease (AD) brains, TREM2 can directly interact with pathological β-amyloid (Aβ) oligomers (Zhong et al., 2018Zhong L. Wang Z. Wang D. Wang Z. Martens Y.A. Wu L. Xu Y. Wang K. Li J. Huang R. et al.Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2).Mol. Neurodegener. 2018; 13: 15Crossref PubMed Scopus (55) Google Scholar) as well as anionic and zwitterionic lipids (Wang et al., 2015Wang Y. Cella M. Mallinson K. Ulrich J.D. Young K.L. Robinette M.L. Gilfillan S. Krishnan G.M. Sudhakar S. Zinselmeyer B.H. et al.TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model.Cell. 2015; 160: 1061-1071Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar) and lipo- and apolipoproteins (LPL, APOE, and CLU/APOJ; Yeh et al., 2016Yeh F.L. Wang Y. Tom I. Gonzalez L.C. Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia.Neuron. 2016; 91: 328-340Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar), which, together with Aβ, form plaques, a hallmark of AD pathology. In addition, in a mouse model of AD, microglia, the myeloid cells of the brain, respond to AD pathology by upregulating APOE, and, specifically, TREM2 activation results in increased production of LPL (Keren-Shaul et al., 2017Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T.K. David E. Baruch K. Lara-Astaiso D. Toth B. et al.A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease.Cell. 2017; 169: 1276-1290.e17Abstract Full Text Full Text PDF PubMed Scopus (1241) Google Scholar). Mechanistically, in AD mouse models, TREM2-deficient microglia indeed show limited expression of APOE (Parhizkar et al., 2019Parhizkar S. Arzberger T. Brendel M. Kleinberger G. Deussing M. Focke C. Nuscher B. Xiong M. Ghasemigharagoz A. Katzmarski N. et al.Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.Nat. Neurosci. 2019; 22: 191-204Crossref PubMed Scopus (139) Google Scholar), and, complementarily, APOE is important for maintenance of the TREM2-dependent microglial phenotype (Krasemann et al., 2017Krasemann S. Madore C. Cialic R. Baufeld C. Calcagno N. El Fatimy R. Beckers L. O’Loughlin E. Xu Y. Fanek Z. et al.The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.Immunity. 2017; 47: 566-581.e9Abstract Full Text Full Text PDF PubMed Scopus (752) Google Scholar, Ulrich et al., 2018Ulrich J.D. Ulland T.K. Mahan T.E. Nyström S. Nilsson K.P. Song W.M. Zhou Y. Reinartz M. Choi S. Jiang H. et al.ApoE facilitates the microglial response to amyloid plaque pathology.J. Exp. Med. 2018; 215: 1047-1058Crossref PubMed Scopus (83) Google Scholar). The complexity of APOE-TREM2 interplay in AD is summarized in detail in recent excellent reviews (Gratuze et al., 2018Gratuze M. Leyns C.E.G. Holtzman D.M. New insights into the role of TREM2 in Alzheimer’s disease.Mol. Neurodegener. 2018; 13: 66Crossref PubMed Scopus (112) Google Scholar, Shi and Holtzman, 2018Shi Y. Holtzman D.M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight.Nat. Rev. Immunol. 2018; 18: 759-772Crossref PubMed Scopus (164) Google Scholar). Similarly, LPL and APOE are induced by a TREM2-dependent mechanism in adipose tissue macrophages as a consequences of high-fat-diet-induced obesity in mice (Jaitin et al., 2019Jaitin D.A. Adlung L. Thaiss C.A. Weiner A. Li B. Descamps H. Lundgren P. Bleriot C. Liu Z. Deczkowska A. et al.Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.Cell. 2019; 178: 686-698.e14Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). These observations suggest that TREM2 activation initiates a cellular signaling loop that promotes production of TREM2 ligands and, therefore, sustains TREM2-dependent activation (Ulland et al., 2017Ulland T.K. Song W.M. Huang S.C.-C. Ulrich J.D. Sergushichev A. Beatty W.L. Loboda A.A. Zhou Y. Cairns N.J. Kambal A. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease.Cell. 2017; 170: 649-663.e13Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, Wang et al., 2015Wang Y. Cella M. Mallinson K. Ulrich J.D. Young K.L. Robinette M.L. Gilfillan S. Krishnan G.M. Sudhakar S. Zinselmeyer B.H. et al.TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model.Cell. 2015; 160: 1061-1071Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar). Second, parallel cellular processes may regulate TREM2 signaling. For example, downstream signaling of TREM2 depends on the presence and availability of DAP12 and DAP10, and this may differ depending on the cell type and state (Cella et al., 2003Cella M. Buonsanti C. Strader C. Kondo T. Salmaggi A. Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals.J. Exp. Med. 2003; 198: 645-651Crossref PubMed Scopus (169) Google Scholar, Otero et al., 2012Otero K. Shinohara M. Zhao H. Cella M. Gilfillan S. Colucci A. Faccio R. Ross F.P. Teitelbaum S.L. Takayanagi H. Colonna M. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.J. Immunol. 2012; 188: 2612-2621Crossref PubMed Scopus (87) Google Scholar, Peng et al., 2010Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci. Signal. 2010; 3: ra38Crossref PubMed Scopus (162) Google Scholar, Ulland et al., 2017Ulland T.K. Song W.M. Huang S.C.-C. Ulrich J.D. Sergushichev A. Beatty W.L. Loboda A.A. Zhou Y. Cairns N.J. Kambal A. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease.Cell. 2017; 170: 649-663.e13Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar). The ITAM motif of DAP12 is phosphorylated by SRC tyrosine kinase upon activation of colony-stimulating factor 1 receptor (CSF1R); therefore, the activity of this signaling will also modulate TREM2-dependent activation (Otero et al., 2009Otero K. Turnbull I.R. Poliani P.L. Vermi W. Cerutti E. Aoshi T. Tassi I. Takai T. Stanley S.L. Miller M. et al.Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin.Nat. Immunol. 2009; 10: 734-743Crossref PubMed Scopus (179) Google Scholar, Zou et al., 2008Zou W. Reeve J.L. Liu Y. Teitelbaum S.L. Ross F.P. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk.Mol. Cell. 2008; 31: 422-431Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Interestingly, humans with a genetic background causing only partial CSF1R activity show a set of symptoms similar to Nasu-Hakola disease patients (Klünemann et al., 2005Klünemann 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.The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.Neurology. 2005; 64: 1502-1507Crossref PubMed Scopus (141) Google Scholar, Satoh et al., 2018Satoh J.-I. Kino Y. Yanaizu M. Saito Y. Alzheimer’s disease pathology in Nasu-Hakola disease brains.Intractable Rare Dis. Res. 2018; 7: 32-36Crossref PubMed Scopus (7) Google Scholar), carrying TREM2-inactivating mutations, suggesting synergy between the two pathways (Hume et al., 2020Hume D.A. Caruso M. Ferrari-Cestari M. Summers K.M. Pridans C. Irvine K.M. Phenotypic impacts of CSF1R deficiencies in humans and model organisms.J. Leukoc. Biol. 2020; 107: 205-219Crossref PubMed Scopus (28) Google Scholar). TREM2- and CSF1R-dependent activation of DAP12 is also key for induction of the β-catenin pathway in differentiating mouse osteoclasts (Otero et al., 2009Otero K. Turnbull I.R. Poliani P.L. Vermi W. Cerutti E. Aoshi T. Tassi I. Takai T. Stanley S.L. Miller M. et al.Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin.Nat. Immunol. 2009; 10: 734-743Crossref PubMed Scopus (179) Google Scholar, Otero et al., 2012Otero K. Shinohara M. Zhao H. Cella M. Gilfillan S. Colucci A. Faccio R. Ross F.P. Teitelbaum S.L. Takayanagi H. Colonna M. TREM2 and β-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.J. Immunol. 2012; 188: 2612-2621Crossref PubMed Scopus (87) Google Scholar). Because TREM2 signaling seems to be most relevant in the context of tissue damage and pathology, it is important to consider the crosstalk between TREM2 signaling and other pathways activated by danger signals. For example, TAM receptors (TYRO3, AXL, and MER) involved in phagocytosis of apoptotic debris can also be engaged on TREM2-expressing microglia, but crosstalk between the two signaling pathways is poorly understood (Savage et al., 2015Savage J.C. Jay T. Goduni E. Quigley C. Mariani M.M. Malm T. Ransohoff R.M. Lamb B.T. Landreth G.E. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease.J. Neurosci. 2015; 35: 6532-6543Crossref PubMed Scopus (85) Google Scholar). Activation of CD33 (SIGLEC-3), a glycoprotein and glycolipid binding receptor with the immunoreceptor tyrosine-based inhibitory motif (ITIM) expressed on myeloid cells, inhibits development of TREM2-dependent microglial phenotype in a mouse model of AD (Griciuc et al., 2019Griciuc A. Patel S. Federico A.N. Choi S.H. Innes B.J. Oram M.K. Cereghetti G. McGinty D. Anselmo A. Sadreyev R.I. et al.TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease.Neuron. 2019; 103: 820-835.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). It is important to note that, in mice, CD33 lacks the ITIM domain and is predicted to associate with activating DAP12. Further, unlike human CD33, mouse CD33 does not recognize α2-3- or α2-6-linked sialic acids, suggesting that human and mouse CD33 may have distinct ligands as well as downstream signaling pathways and functions, including interaction with the TREM2-dependent cascade (Bhattacherjee et al., 2019Bhattacherjee A. Rodrigues E. Jung J. Luzentales-Simpson M. Enterina J.R. Galleguillos D. St Laurent C.D. Nakhaei-Nejad M. Fuchsberger F.F. Streith L. et al.Repression of phagocytosis by human CD33 is not conserved with mouse CD33.Commun. Biol. 2019; 2: 450Crossref PubMed Scopus (24) Google Scholar, Brinkman-Van der Linden et al., 2003Brinkman-Van der Linden E.C. Angata T. Reynolds S.A. Powell L.D. Hedrick S.M. Varki A. CD33/Siglec-3 binding specificity, expression pattern, and consequences of gene deletion in mice.Mol. Cell. Biol. 2003; 23: 4199-4206Crossref PubMed Scopus (69) Google Scholar, Hammond et al., 2019Hammond T.R. Marsh S.E. Stevens B. Immune signaling in neurodegeneration.Immunity. 2019; 50: 955-974Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Macauley et al., 2014Macauley M.S. Crocker P.R. Paulson J.C. Siglec-mediated regulation of immune cell function in disease.Nat. Rev. Immunol. 2014; 14: 653-666Crossref PubMed Scopus (466) Google Scholar). Finally, TREM2 signaling via DAP12 antagonizes Toll-like receptor (TLR) expression and inflammatory cytokine production following TLR engagement in cultured mouse macrophages, and, conversely, TREM2 expression is abrogated by pro-inflammatory signaling of LPS (a TLR4 ligand) or interferon gamma (IFNγ) (Gao et al., 2013Gao X. Dong Y. Liu Z. Niu B. Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide.Mol. Med. Rep. 2013; 7: 921-926Crossref PubMed Scopus (37) Google Scholar, Hamerman et al., 2006Hamerman J.A. Jarjoura J.R. Humphrey M.B. Nakamura M.C. Seaman W.E. Lanier L.L. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12.J. Immunol. 2006; 177: 2051-2055Crossref PubMed Scopus (290) Google Scholar, Ito and Hamerman, 2012Ito H. Hamerman J.A. TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells.Eur. J. Immunol. 2012; 42: 176-185Crossref PubMed Scopus (106) Google Scholar, Turnbull et al., 2006Turnbull I.R. Gilfillan S. Cella M. Aoshi T. Miller M. Piccio L. Hernandez M. Colonna M. Cutting edge: TREM-2 attenuates macrophage activation.J. Immunol. 2006; 177: 3520-3524Crossref PubMed Scopus (387) Google Scholar). The latter phenomenon is, at least in part, an effect of TREM2 shedding; the α-secretases disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and ADAM10 cleave human TREM2 at the H157-S158 peptide bond, which results in release of soluble TREM2 (sTREM2). Further cleavage of the truncated transmembrane portion of TREM2 by γ-secretase releases DAP12 and therefore blocks TREM2 signaling (Feuerbach et al., 2017Feuerbach D. Schindler P. Barske C. Joller S. Beng-Louka E. Worringer K.A. Kommineni S. Kaykas A. Ho D.J. Ye C. et al.ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157.Neurosci. Lett. 2017; 660: 109-114Crossref PubMed Scopus (38) Google Scholar, Schlepckow et al., 2017Schlepckow K. Kleinberger G. Fukumori A. Feederle R. Lichtenthaler S.F. Steiner H. Haass C. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.EMBO Mol. Med. 2017; 9: 1356-1365Crossref PubMed Scopus (78) Google Scholar, Schlepckow et al., 2020Schlepckow K. Monroe K.M. Kleinberger G. Cantuti-Castelvetri L. Parhizkar S. Xia D. Willem M. Werner G. Pettkus N. Brunner B. et al.Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.EMBO Mol. Med. 2020; 12: e11227Crossref PubMed Scopus (44) Google Scholar, Thornton et al., 2017Thornton P. Sevalle J. Deery M.J. Fraser G. Zhou Y. Ståhl S. Franssen E.H. Dodd R.B. Qamar S. Gomez Perez-Nievas B. et al.TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant.EMBO Mol. Med. 2017; 9: 1366-1378Crossref PubMed Scopus (52) Google Scholar). Remarkably, sTREM2 as well as the remaining membrane-bound part of the TREM2 receptor display biological activities, as we describe in the following sections. Another level of TREM2 regulation is through control of its expression levels. Stimulation of the nuclear receptors peroxisome proliferator-activated receptor (PPARγ and PPARδ), liver X receptor (LXR), and retinoid X receptor (RXR) has been proposed to promote expression of TREM2 and other phagocytosis-related receptors in mice (Daniel et al., 2014Daniel B. Nagy G. Hah N. Horvath A. Czimmerer Z. Poliska S. Gyuris T. Keirsse J. Gysemans C. Van Ginderachter J.A. et al.The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.Genes Dev. 2014; 28: 1562-1577Crossref PubMed Scopus (60) Google Scholar, Savage et al., 2015Savage J.C. Jay T. Goduni E. Quigley C. Mariani M.M. Malm T. Ransohoff R.M. Lamb B.T. Landreth G.E. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease.J. Neurosci. 2015; 35: 6532-6543Crossref PubMed Scopus (85) Google Scholar). Production of TREM2 protein in mice has been suggested to be post-transcriptionally downregulated by the microRNA miR-34a, which is expressed upon nuclear factor κB (NF-κB) activation and is present at high levels in degenerating brains in AD patients and the eyes of patients with age-related macular degeneration (Bhattacharjee et al., 2016Bhattacharjee S. Zhao Y. Dua P. Rogaev E.I. Lukiw W.J. microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration.PLoS ONE. 2016; 11 (e0150211)Crossref Scopus (77) Google Scholar, Zhao et al., 2013Zhao Y. Bhattacharjee S. Jones B.M. Dua P. Alexandrov P.N. Hill J.M. Lukiw W.J. Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a.Neuroreport. 2013; 24: 318-323Crossref PubMed Scopus (71) Google Scholar), niches where TREM2 seems to play an important role, as we describe in the following sections. In summary, activation and regulation of the TREM2 pathway is a complex process critically dependent on tissue context and intracellular state. Further studies focused on in vivo regulation of TREM2 signaling are needed to decipher how TREM2 and its co-receptor responses depend on a complex context of damaged tissues, including a multitude of ligands that can interact with other receptors, and how TREM2 signaling is incorporated within other cellular pathways. We also need to better understand the downstream mechanisms of TREM2 activation—the molecular links between TREM2 engagement and intricate TREM2-dependent phenotypic transformations. First observations pointing to the importance of TREM2 for human health were made in the context of Nasu-Hakola disease (NHD), also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), a fatal disease characterized by progressive pre-senile dementia associated with recurrent bone fractures because of cystic lesions. Genetic studies identified loss-of-function mutations in TREM2 and DAP12 as the disease cause (Klünemann et al., 2005Klünemann 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.The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.Neurology. 2005; 64: 1502-1507Crossref PubMed Scopus (141) Google Scholar). The fact that NHD patients develop a consistent, variant-dependent phenotype suggests that TREM2 plays an important physiological role in tissue development and/or maintenance, at least in the context of particular niches, the brain and bone, by controlling the function of TREM2-expressing myeloid cells: microglia and osteoclasts (Figure 2A). Investigating TREM2 expression across human tissues analyzed by single-cell RNA sequencing (scRNA-seq) studies and gathered into a human cell landscape (Han et al., 2020Han X. Zhou Z. Fei L. Sun H. Wang R. Chen Y. Chen H. Wang J. Tang H. Ge W. et al.Construction of a human cell landscape at single-cell level.Nature. 2020; (Published online March 25, 2020)https://doi.org/10.1038/s41586-020-2157-4Crossref Scopus (132) Google Scholar) confirmed that TREM2 is expressed in physiology in a small set of tissue-specific macrophages. In addition to human microglia, this analysis identified TREM2 expression in macrophages of adipose tissue, adrenal gland, and placenta (Figure 2B). Although the role of TREM2 in adipose tissue was recently dissected in the context of obesity in mice and humans, as we describe later in detail (Jaitin et al., 2019Jaitin D.A. Adlung L. Thaiss C.A. Weiner A. Li B. Descamps H. Lundgren P. Bleriot C. Liu Z. Deczkowska A. et al.Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.Cell. 2019; 178: 686-698.e14Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), the roles of TREM2 in regulation of macrophage activity in adrenal gland and placenta remain to be established. Defects in differentiation and survival of myeloid cells from NHD patients and mice lacking TREM2 or DAP12 have been reported (Cella et al., 2003Cella M. Buonsanti C. Strader C. Kondo T. Salmaggi A. Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals.J. Exp. Med. 2003; 198: 645-651Crossref PubMed Scopus (169) Google Scholar, Otero et al., 2009Otero K. Turnbull I.R. Poliani P.L. Vermi W. Cerutti E. Aoshi T. Tassi I. Takai T. Stanley S.L. Miller M. et al.Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin.Nat. Immunol. 2009; 10: 734-743Crossref PubMed Scopus (179) Google Scholar, Zou et al., 2008Zou W. Reeve J.L. Liu Y. Teitelbaum S.L. Ross F.P. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk.Mol. Cell. 2008; 31: 422-431Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). However, loss of TREM2-DAP12 signaling in mice causes only a mild phenotype; mice lacking TREM2 show osteopenia and lower numbers of microglia in defined central nervous system (CNS) areas, but only at an older age, and the mice never show CNS or bone lesions characteristic of NHD patients (Otero et al., 2012O