Affinage

TREM2

Triggering receptor expressed on myeloid cells 2 · UniProt Q9NZC2

Length
230 aa
Mass
25.4 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TREM2 is a myeloid cell surface receptor that senses diverse damage- and pathogen-associated molecular patterns—including anionic lipids, apolipoproteins (APOE, CLU), amyloid-β oligomers, TDP-43, phosphatidylserine, sphingolipids, and mycolic acids—and transduces signals through the adaptor DAP12 to activate SYK, PI3K/Akt, mTOR, and Wnt/β-catenin pathways, thereby governing macrophage and microglial phagocytosis, survival, proliferation, metabolic fitness, and inflammatory calibration (PMID:25728668, PMID:29518356, PMID:28802038, PMID:28077724, PMID:16951310). TREM2 is proteolytically shed by ADAM10/17 to generate soluble sTREM2, and disease-associated mutations (R47H, R62H) impair ligand binding, receptor maturation/shedding, and downstream signaling, disrupting microglial barrier function around amyloid plaques and myelin debris (PMID:24990881, PMID:30341064, PMID:32154671). Beyond the CNS, TREM2 programs lipid-associated macrophage (LAM) transcriptional states required for cholesterol handling and efferocytosis in adipose tissue, atherosclerotic lesions, and liver fibrosis, and it modulates anti-tumor immunity in a tissue-context-dependent manner—immunosuppressive in peripheral tumors yet immunoprotective in glioblastoma (PMID:31257031, PMID:38974464, PMID:32783915, PMID:38788719). Loss-of-function TREM2 mutations cause Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) and frontotemporal dementia-like syndromes, and the R47H variant is a major genetic risk factor for Alzheimer's disease (PMID:24990881, PMID:34851693).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2006 High

    Establishing TREM2 as an anti-inflammatory brake: TREM2 signals through DAP12 to attenuate TLR-induced cytokine production in macrophages, resolving the question of why DAP12-deficient macrophages are hyperinflammatory.

    Evidence TREM2 KO macrophages stimulated with multiple TLR ligands; epistasis with DAP12 KO

    PMID:16951310

    Open questions at the time
    • Ligand identity for TREM2 unknown at this point
    • Mechanism of cytokine suppression downstream of DAP12 unresolved
    • Tissue-specific roles beyond macrophages untested
  2. 2007 Medium

    Demonstrating TREM2/DAP12 signaling is required for osteoclast differentiation extended TREM2 function beyond inflammation to myeloid cell fate decisions.

    Evidence In vitro osteoclastogenesis from human TREM2/DAP12-deficient precursors

    PMID:17966394

    Open questions at the time
    • Single in vitro system without in vivo bone phenotype characterization
    • Downstream differentiation signals not identified
    • Unclear if TREM2 vs DAP12 deficiency is rate-limiting
  3. 2014 High

    Linking disease mutations to molecular mechanism: FTD-associated TREM2 missense mutations abolish ADAM protease-mediated shedding, reduce maturation, and impair phagocytosis, explaining the near-absence of sTREM2 in patient biofluids.

    Evidence Cell-based TREM2 maturation/shedding assays, phagocytosis assays, CSF/plasma sTREM2 measurement in patients

    PMID:24990881

    Open questions at the time
    • Identity of ADAM10 vs ADAM17 as dominant sheddase not disambiguated
    • Whether shedding loss is cause or correlate of neurodegeneration unclear
  4. 2014 Medium

    Identifying PI3K/Akt as a key intracellular effector: TREM2 promotes bacterial killing through PI3K/Akt-dependent ROS production, establishing the first defined signaling axis downstream of TREM2.

    Evidence siRNA knockdown and overexpression in macrophages, PI3K agonist rescue of killing defect

    PMID:24383713

    Open questions at the time
    • Single pathogen system
    • No direct demonstration of TREM2–PI3K physical interaction
    • SYK involvement not yet tested
  5. 2015 High

    Identifying TREM2's physiological ligands: TREM2 senses anionic and zwitterionic lipids on damaged neurons and Aβ-associated membranes; TREM2 deficiency causes failed microglial clustering around plaques and microglial apoptosis in AD mice, with R47H impairing lipid detection.

    Evidence Lipid-binding assays, 5XFAD mice with TREM2 KO/haploinsufficiency, microglial imaging

    PMID:25728668

    Open questions at the time
    • Structural basis of lipid recognition unknown
    • Which specific lipid species dominate in vivo undetermined
    • Contribution of protein vs lipid ligands to in vivo phenotype unclear
  6. 2015 Medium

    sTREM2 identified as a bioactive species: IL-13 and DAP12 promote TREM2 cleavage, and the resulting sTREM2 acts in a feed-forward manner to prevent macrophage apoptosis during viral infection.

    Evidence TREM2 KO mice with Sendai virus, sTREM2 measurement, apoptosis assays

    PMID:25897174

    Open questions at the time
    • Receptor for sTREM2 not identified
    • Single viral infection model
    • Whether sTREM2 signals through same or different receptor unclear
  7. 2016 High

    Apolipoprotein binding expanded TREM2 ligand repertoire: unbiased screen identified APOE and CLU as TREM2 ligands; TREM2 mediates uptake of Aβ-lipoprotein complexes, and disease mutations impair this binding and uptake.

    Evidence Protein microarray, Co-IP, overexpression uptake assays, Trem2 KO microglia, human macrophage assays

    PMID:27477018

    Open questions at the time
    • Whether TREM2 binds lipidated vs free APOE differently not resolved
    • Relative contribution of lipid vs protein moieties in lipoprotein recognition unclear
  8. 2017 High

    Three converging studies established TREM2's role in microglial metabolic fitness, survival via Wnt/β-catenin, and the TREM2-APOE axis for microglial state switching: TREM2 deficiency causes mTOR-dependent metabolic derailment with reduced ATP and aberrant autophagy; TREM2 stabilizes β-catenin via Akt/GSK3β to promote survival; and TREM2 drives APOE signaling to switch microglia from homeostatic to neurodegenerative phenotype.

    Evidence Metabolomics/RNA-seq with cyclocreatine rescue in AD mice; β-catenin stability and Wnt agonist rescue in KO microglia; transcriptomics in ALS/AD/MS mouse models with APOE pathway targeting

    PMID:28077724 PMID:28802038 PMID:28930663

    Open questions at the time
    • How TREM2 engages mTOR mechanistically not fully resolved
    • Whether Wnt/β-catenin and mTOR axes operate independently or converge unclear
    • Causal direction between TREM2 and APOE induction in disease not established
  9. 2018 High

    Direct nanomolar Aβ binding and signaling cascade defined: TREM2 binds Aβ oligomers directly with high affinity; engagement enhances TREM2-DAP12 association and triggers SYK/GSK3β phosphorylation; R47H/R62H variants retain Aβ binding but lose downstream signaling and internalization capacity.

    Evidence SPR, ELISA, NFAT reporter, internalization assays, Co-IP for TREM2-DAP12, phosphorylation assays in KO microglia

    PMID:29518356 PMID:30341064

    Open questions at the time
    • Structural basis of how R47H retains Aβ binding yet loses signaling unknown
    • Relative importance of Aβ vs lipid ligands in AD pathogenesis not resolved
  10. 2019 High

    TREM2 established as a master regulator of lipid-associated macrophage (LAM) programs and amyloid plaque containment: TREM2 loss increases amyloid seeding due to failed microglial plaque barrier; in adipose tissue, TREM2 is required for LAM transcriptional programming, and its loss causes metabolic syndrome.

    Evidence Trem2 KO mice with longitudinal amyloid PET and plaque proteomics; scRNA-seq of adipose macrophages with metabolic phenotyping; genetic epistasis with CD33

    PMID:30617257 PMID:31257031 PMID:31301936

    Open questions at the time
    • Whether LAM programming is identical across tissues undetermined
    • CD33-TREM2 physical interaction not demonstrated
    • Whether metabolic phenotype is cell-autonomous or paracrine unclear
  11. 2020 High

    TREM2 controls cholesterol metabolism after myelin phagocytosis and shapes tumor immunity: TREM2-deficient microglia accumulate toxic cholesteryl esters after demyelination; in tumors, TREM2 drives immunosuppressive myeloid programming that suppresses CD8+ T cell function; anti-TREM2 antibody 4D9 stabilizes surface TREM2 and activates SYK signaling in vivo.

    Evidence RNA-seq/lipidomics with iPSC microglia and demyelination model; INs-seq in Trem2 KO tumor models; antibody characterization with phospho-SYK and in vivo AD model treatment

    PMID:31902528 PMID:32154671 PMID:32783915

    Open questions at the time
    • Whether cholesterol handling defect is specific to myelin-derived cholesterol unknown
    • Tumor context-dependency of TREM2 immunosuppressive role not explained mechanistically
    • Long-term in vivo effects of anti-shedding antibodies not assessed
  12. 2021 High

    Expanding ligand repertoire and variant signaling: TREM2 directly binds mycolic acids and TDP-43, and R47H hyperactivates AKT, which can be therapeutically targeted to rescue tauopathy-associated synapse loss.

    Evidence SPR/MS for TDP-43 binding with KO mice; lipid-binding assays for mycolic acids with in vivo mycobacterial infection; R47H knock-in tauopathy mice with AKT inhibitor MK-2206 rescue

    PMID:33863908 PMID:34851693 PMID:34916658

    Open questions at the time
    • Whether TDP-43 is a physiological TREM2 ligand in living brain unclear
    • How R47H causes AKT hyperactivation while losing other signaling functions paradoxical and unresolved
    • TMEM59 interaction validation limited to single Co-IP study
  13. 2022 High

    TREM2 constrains tau spreading and is counter-regulated by LILRB2: TREM2 deletion enhances exosome-mediated tau propagation; LILRB2 co-ligates with TREM2 on shared ligands to inhibit TREM2 signaling, and LILRB2 blockade rescues microglial phagocytosis and plaque clearance.

    Evidence AAV-tau injection in Trem2 KO mice with exosome tau FRET reporter; LILRB2 antagonist antibody in iPSC microglia and 5XFAD mice

    PMID:35717259 PMID:36056435

    Open questions at the time
    • Whether LILRB2-TREM2 crosstalk operates in non-AD contexts unknown
    • Mechanism by which TREM2 controls exosome tau sorting not identified
    • ApoE4 epistasis with TREM2 in tau spreading not fully resolved
  14. 2023 High

    TREM2 function extended to cardiac, hepatic, antiviral, developmental, and tumor contexts: TREM2+ cardiac macrophages scavenge damaged mitochondria; TREM2 is required for MASH fibrosis regression via collagen degradation; TREM2 augments cGAS-STING antiviral signaling; TREM2 is needed for neuronal metabolic maturation during development; and TREM2+ macrophages suppress NK cells in lung tumors via IL-18BP/IL-15 axis.

    Evidence Trem2 KO in sepsis/cardiac models, MASH regression models with scRNA-seq, iPSC microglia with HSV1 infection, developmental Trem2 KO with electron microscopy and metabolomics, lung adenocarcinoma KO models

    PMID:36635449 PMID:37081148 PMID:37595041 PMID:38159572 PMID:39172787

    Open questions at the time
    • Whether cardiac and hepatic TREM2 ligands differ from CNS ligands unknown
    • cGAS-STING augmentation mechanism not defined at the molecular level
    • How microglial TREM2 non-cell-autonomously controls neuronal mitochondria during development unclear
  15. 2023 Medium

    sTREM2 splice isoforms and NLRP3-driven shedding revealed new regulatory layers: alternatively spliced TREM2 isoforms lacking transmembrane domains are secreted and inhibit LTP via a GABAA-dependent mechanism; poly-GA aggregates activate NLRP3/IL-1β to promote ADAM10-mediated TREM2 shedding.

    Evidence In vitro translation/secretion assays, hippocampal slice LTP with picrotoxin rescue; poly-GA mouse model with NLRP3 inhibitor MCC950

    PMID:36800288 PMID:36805764

    Open questions at the time
    • Receptor for sTREM2 in LTP modulation unidentified
    • Mechanism linking sTREM2 to GABAA signaling unknown
    • Whether NLRP3-driven shedding is generalizable beyond C9orf72 context unclear
  16. 2024 High

    TREM2 in cardiovascular disease and cancer refined: TREM2 programs foamy macrophage specification and efferocytosis in atherosclerosis; TREM2 drives post-efferocytosis metabolic reprogramming via SYK-SMAD4-itaconate in myocardial infarction; CNS-enriched sphingolipids activate TREM2 to mount anti-tumor responses in GBM, opposite to peripheral tumors.

    Evidence CRISPR screens and myeloid-specific KO in atherosclerosis; metabolomics with macrophage-specific KO in MI; sphingolipid binding assays with AAV-TREM2 in GBM models

    PMID:38182899 PMID:38646596 PMID:38788719 PMID:38974464

    Open questions at the time
    • Structural determinants of sphingolipid vs other lipid recognition not resolved
    • Why TREM2 is immunosuppressive in peripheral tumors but immunoprotective in GBM remains mechanistically unexplained
    • Whether itaconate production is a universal post-efferocytosis output unclear
  17. 2025 High

    TREM2 identified as a key brake on NLRP3/NF-κB/IL-1β inflammasome in tumor-associated macrophages: TREM2 depletion combined with microbial LPS unleashes IL-1β-driven pathogenic inflammation that accelerates pancreatic cancer.

    Evidence KPPC;Trem2-/- spontaneous PDAC model with scRNA-seq, IL-1β inhibition and microbiome ablation rescue

    PMID:39956331

    Open questions at the time
    • Whether TREM2 directly inhibits NLRP3 assembly or acts upstream unclear
    • Microbiome composition changes in TREM2 KO not defined
    • Generalizability to other GI cancers untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of TREM2's promiscuous ligand recognition; the receptor and signaling mechanism for soluble sTREM2; why TREM2 exerts opposing immunological roles in CNS versus peripheral tumors; and how TREM2 non-cell-autonomously regulates neuronal metabolism during development.
  • No high-resolution structure of TREM2 with lipid or protein ligands
  • sTREM2 receptor unknown
  • Tissue-context determinants of pro- vs anti-inflammatory TREM2 output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 3 GO:0038024 cargo receptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ADAM10APOECLULILRB2SYKTMEM59TYROBP
Complex memberships
TREM2/DAP12

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 TREM2 signals through the adaptor protein DAP12 and functions to attenuate macrophage activation by inhibiting cytokine production in response to TLR ligands (LPS, zymosan, CpG); TREM2-deficient macrophages produce more cytokines, and TREM2 accounts for the increased cytokine production previously reported in DAP12-deficient macrophages. TREM2 knockout mice, TLR ligand stimulation assays, cytokine measurement Journal of immunology High 16951310
2007 TREM2 transduces intracellular signals through DAP12 and is required for normal osteoclastogenesis; human TREM2/DAP12-deficient pre-osteoclast precursors fail to differentiate into mature osteoclasts with bone resorptive activity in vitro. In vitro osteoclast differentiation assay with human TREM2/DAP12-deficient precursors Advances in experimental medicine and biology Medium 17966394
2014 TREM2 missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases (α-secretases), and impair phagocytic activity; as a consequence of reduced shedding, TREM2 is virtually absent in CSF and plasma of affected patients. Cell-based assays of TREM2 maturation and shedding, phagocytosis assays, CSF/plasma measurement in patients Science translational medicine High 24990881
2014 TREM2 promotes macrophage-mediated intracellular killing of Pseudomonas aeruginosa by enhancing reactive oxygen species (ROS) production via the PI3K/Akt signaling pathway; TREM2 silencing inhibits Akt phosphorylation and bacterial killing, whereas PI3K agonism rescues the killing defect. TREM2 siRNA knockdown, overexpression, phagocytosis/killing assays, ROS measurement, PI3K inhibitor/agonist treatments, Western blot for Akt phosphorylation Scandinavian journal of immunology Medium 24383713
2015 TREM2 senses a broad array of anionic and zwitterionic lipids (damage-associated lipid patterns) associated with fibrillar Aβ in lipid membranes and on damaged neurons; TREM2 deficiency and haploinsufficiency cause dysfunctional microglial clustering around Aβ plaques and microglial apoptosis in the 5XFAD mouse model; the R47H AD-risk mutation impairs TREM2 detection of lipid ligands. 5XFAD mouse model with TREM2 KO/haploinsufficiency, lipid-binding assays, microglial clustering and apoptosis analysis Cell High 25728668
2015 TREM2 promotes macrophage survival; viral replication increases TREM2 levels including the soluble form (sTREM2), and IL-13 and DAP12 promote TREM2 cleavage to sTREM2, which acts in a feed-forward manner to prevent macrophage apoptosis. Mouse model of Sendai virus infection, TREM2 KO mice, measurement of soluble TREM2, apoptosis assays The Journal of experimental medicine Medium 25897174
2016 TREM2 binds lipoprotein particles (LDL) and apolipoproteins (APOE, CLU/APOJ) identified by unbiased protein microarray; TREM2 overexpression enhances uptake of LDL, CLU, and APOE; Aβ-lipoprotein complexes are taken up by microglia in a TREM2-dependent fashion; disease-associated TREM2 mutations abolish or reduce ligand binding and impair uptake. Protein microarray screen, Co-IP/pulldown, overexpression in heterologous cells, Trem2 KO microglia, human macrophage uptake assays Neuron High 27477018
2017 TREM2 deficiency causes defective mTOR signaling, leading to aberrant autophagy, reduced ATP levels, and impaired biosynthetic pathways in microglia; this metabolic derailment can be rescued in vitro by Dectin-1 (which elicits TREM2-like signals) or cyclocreatine, and dietary cyclocreatine restores microglial clustering and reduces neuronal dystrophy in TREM2-deficient AD mice. Metabolomics + RNA-seq, TREM2-deficient mouse and human AD samples, in vitro rescue experiments, in vivo dietary cyclocreatine treatment Cell High 28802038
2017 TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway; TREM2 stabilizes β-catenin by inhibiting its degradation via Akt/GSK3β; TREM2 deficiency reduces viability and proliferation of primary microglia and induces G1/S cell cycle arrest; treatment with Wnt pathway activators (Wnt3a, LiCl, TDZD-8) rescues microglia survival in Trem2-deficient microglia and brain. TREM2 KD/KO in vitro and in vivo, cell viability/proliferation assays, β-catenin stability assays, pharmacological rescue with Wnt agonists The Journal of neuroscience High 28077724
2017 TREM2 induces APOE signaling and drives a switch from homeostatic to neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons; targeting the TREM2-APOE pathway restores homeostatic microglial signature in ALS and AD mouse models and prevents neuronal loss in acute neurodegeneration models. Mouse models of ALS, MS, AD; microglial transcriptomics; APOE targeting; genetic and pharmacological manipulation Immunity High 28930663
2018 TREM2 directly binds β-amyloid (Aβ) oligomers with nanomolar affinity; TREM2 deficiency impairs Aβ degradation; Aβ-induced microglial responses (depolarization, K+ current, cytokine expression, migration, proliferation, apoptosis, morphological changes) are TREM2-dependent; Aβ enhances TREM2 interaction with DAP12, regulating downstream phosphorylation of SYK and GSK3β. Direct binding assays, primary microglial culture, mouse brain experiments, Co-IP for TREM2-DAP12, phosphorylation assays for SYK and GSK3β, TREM2 KO mice Neuron High 29518356
2018 TREM2 interacts directly with various forms of Aβ, with highest affinity for soluble Aβ42 oligomers (slow dissociation); Aβ pre-incubation blocks APOE interaction with TREM2; AD-associated TREM2 variants (R47H, R62H) show equivalent Aβ binding affinity but loss-of-function in terms of downstream NFAT signaling and Aβ42 internalization. Multiple binding assays (SPR, ELISA-based), NFAT reporter assay, Aβ42 internalization assays in cells expressing TREM2 variants EMBO molecular medicine High 30341064
2019 Loss of functional TREM2 increases amyloid plaque seeding due to reduced microglial clustering around newly seeded plaques and reduced plaque-associated ApoE; microglia are identified as one origin of plaque-associated ApoE; longitudinal PET demonstrates accelerated early amyloidogenesis in Trem2 loss-of-function mutants. Trem2 KO mouse models, microglia depletion, proteomic analyses of plaques, longitudinal amyloid small-animal PET, human AD brain analysis Nature neuroscience High 30617257
2019 TREM2 is required for TREM2+ lipid-associated macrophage (LAM) transcriptional programming in adipose tissue; genetic ablation of Trem2 inhibits the downstream LAM molecular program, leading to adipocyte hypertrophy, systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. Single-cell RNA sequencing, Trem2 KO mice, metabolic phenotyping Cell High 31257031
2019 TREM2 acts downstream of CD33 in modulating microglial function: CD33 knockout reduces Aβ pathology in an effect that requires TREM2; genes related to phagocytosis and signaling upregulated in 5xFAD;CD33-/- microglia depend on the presence of TREM2, establishing TREM2 downstream of CD33 by genetic epistasis. Double-knockout mouse models (5xFAD;CD33-/-;TREM2-/-), RNA-seq profiling, epistasis analysis Neuron High 31301936
2020 TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in pathogenic cholesteryl ester (CE) accumulation; TREM2 acts as a key transcriptional regulator of cholesterol transport and metabolism; CE accumulation is rescued by ACAT1 inhibitor and LXR agonist. Chronic demyelination mouse model, TREM2 KO mice, RNA-seq + lipidomics, human iPSC-derived microglia, pharmacological rescue Neuron High 31902528
2020 Genetic ablation of Trem2 in tumor-bearing mice inhibits accumulation of intra-tumoral Arg1+ Trem2+ regulatory myeloid (Mreg) cells, leading to decreased dysfunctional CD8+ T cells and reduced tumor growth, identifying TREM2 as a driver of the immunosuppressive myeloid program in tumors. INs-seq (scRNA-seq + intracellular protein activity), Trem2 KO mouse tumor models, CD8+ T cell functional analysis Cell High 32783915
2020 Monoclonal antibody 4D9 targeting the TREM2 stalk region stabilizes TREM2 on the cell surface, reduces ADAM10/17-mediated shedding, and concomitantly activates phospho-SYK signaling; in vivo, 4D9 reduced amyloidogenesis and enhanced microglial TREM2 expression in AD mouse model. Antibody panel screening, surface TREM2 quantification, phospho-SYK assay, in vitro phagocytosis assays, in vivo AD mouse model treatment EMBO molecular medicine High 32154671
2021 TREM2 recognizes non-glycosylated mycolic acids (MAs) from mycobacteria via a TREM2/DAP12-dependent but CARD9-independent mechanism; this suppresses anti-mycobacterial immunity by recruiting iNOS-negative, mycobacterium-permissive macrophages; TREM2 deletion enhances Mincle-induced macrophage activation and accelerates mycobacterial elimination, indicating TREM2 is exploited by mycobacteria for immune evasion. Lipid-binding assays, TREM2/DAP12 KO macrophages, in vitro macrophage activation assays, in vivo mycobacterial infection models Nature communications High 33863908
2021 TREM2 directly interacts with TDP-43 as demonstrated by mass spectrometry and surface plasmon resonance (SPR) in vitro and in vivo; TREM2 deficiency impairs phagocytic clearance of pathological TDP-43 by microglia and enhances neuronal damage; a TREM2-dependent CD11c-high microglial subpopulation with phagocytic activity is induced by human TDP-43. Mass spectrometry, SPR analysis, TREM2-deficient mouse models, mass cytometry, human ALS tissue analysis Nature neuroscience High 34916658
2021 The R47H TREM2 variant induces hyperactivation of AKT signaling downstream of TREM2; pharmacological AKT inhibition (MK-2206) largely reverses enhanced inflammatory signatures in primary R47H microglia and rescues tauopathy-induced synapse loss in R47H heterozygous tauopathy mice. Human AD snRNA-seq, R47H knock-in tauopathy mouse model, scRNA-seq, pharmacological AKT inhibition with MK-2206 Science translational medicine High 34851693
2021 TREM2 interacts with TMEM59 (a type I transmembrane protein); TREM2 overexpression reduces TMEM59 protein levels by promoting its degradation; elevated TMEM59 in Trem2-deficient microglia contributes to impaired survival, proliferation, migration, phagocytosis, dysregulated autophagy, and metabolism. Co-IP, overexpression and KO in microglia, protein degradation assays, functional microglial assays Cell death & disease Medium 32826884
2022 TREM2 deletion enhances tau spreading from the medial entorhinal cortex to hippocampus; Trem2 deletion in microglia enhances intraneuronal tau dispersion via exosomes — Trem2 KO microglia show enhanced tau distribution to endosomal/pre-exosomal compartments and exosomes from Trem2 KO microglia have elevated tau levels and enhanced tau-seeding capacity. AAV-P301L tau injection model, Trem2 KO mice, microfluidic dispersion assay, exosome isolation and characterization, tau FRET reporter assay, proteomic analysis Molecular neurodegeneration High 36056435
2022 LILRB2 (an inhibitory receptor with ITIM motifs) co-ligates with TREM2 on shared ligands (Aβ oligomers, phosphatidylserine) and inhibits TREM2 signaling; a LILRB2 antagonist antibody (Ab29) blocks this inhibition, enhancing TREM2 signaling, microglia phagocytosis, migration, and amyloid plaque clearance in vivo in 5XFAD mice. Co-ligation experiments in iPSC-derived microglia, LILRB2 antagonist antibody, phagocytosis and migration assays, in vivo stereotaxic microglia grafting in 5XFAD mice Molecular neurodegeneration High 35717259
2022 TREM2-deficient microglia in TREM2-independent microgliosis context (with ApoE4) show exacerbated tau-mediated neurodegeneration; this is epistatic to ApoE4 — TREM2 KO in P301S/ApoE4 mice worsens, rather than attenuates, neurodegeneration, revealing that TREM2-independent microgliosis facilitates neurodegeneration in the presence of ApoE4. Double-mutant mouse models (P301S tau × ApoE4 × TREM2 KO), transcriptomics, neuropathology Neuron High 36368315
2023 TREM2 expression in microglia is required for normal bioenergetic profile of pyramidal neurons during development; in Trem2 KO mice, developing CA1 hippocampal neurons display compromised energetic metabolism, reduced mitochondrial mass, abnormal organelle ultrastructure, and delayed neuronal maturation. Trem2 KO mice, metabolic profiling, electron microscopy of mitochondria, single-cell/nucleus transcriptomics, hippocampal subfield-specific analysis Immunity High 38159572
2023 TREM2 splice isoforms (TREM2-222 and TREM2-219) lacking a transmembrane domain are translated and secreted as soluble TREM2 (sTREM2); all sTREM2 species inhibit long-term potentiation (LTP) induction in hippocampal brain slices, and this effect is abolished by GABAA receptor antagonist picrotoxin. In vitro translation and secretion assays, LTP electrophysiology in hippocampal slices, pharmacological blockade with picrotoxin Genome medicine Medium 36805764
2023 Poly-GA proteins (from C9orf72 GGGGCC repeats) activate the microglial NLRP3 inflammasome to produce IL-1β, which promotes ADAM10-mediated TREM2 cleavage and inhibits phagocytosis of poly-GA; NLRP3 inhibitor MCC950 reduces TREM2 cleavage and poly-GA aggregates, alleviating motor deficits in poly-GA mice. Mouse model of poly-GA aggregation, NLRP3 inhibitor treatment (MCC950), ADAM10 cleavage assays, phagocytosis assays, motor behavioral testing Cell reports Medium 36800288
2023 TREM2 mediates phagocytosis of glioma cells via SYK signaling; TREM2+ myeloid cells display enhanced tumor uptake compared to TREM2- cells, and this phagocytic function is mechanistically linked to TREM2-SYK axis. Single-cell RNA-seq, flow cytometry, in vivo glioma models, in vitro phagocytosis assays with SYK inhibition Neuro-oncology Medium 38237157
2023 TREM2 macrophages suppress NK cell accumulation and cytolytic activity in lung tumors by modulating IL-18/IL-18BP decoy interactions and IL-15 production; Trem2 genetic deletion rescues NK cell accumulation and enables NK cell-mediated tumor regression. Murine lung adenocarcinoma model, Trem2 KO mice, NK cell functional assays, cytokine analysis (IL-18, IL-18BP, IL-15) Nature immunology High 37081148
2023 TREM2 is required for antiviral defense in microglia: TREM2 is important for virus-induced IFNB induction through the DNA-sensing cGAS-STING pathway and for phagocytosis of HSV1-infected neurons; TREM2 augments STING signaling and activation of downstream TBK1 and IRF3; TREM2 depletion increases susceptibility to HSV1 infection. hiPSC-derived microglia, TREM2 depletion, HSV1 infection assays, cGAS-STING pathway analysis, microglia-neuron cocultures, mouse brain infection model Science advances High 37595041
2023 TREM2hi cardiac resident macrophages actively scavenge cardiomyocyte-ejected dysfunctional mitochondria; Trem2 deficiency in macrophages impairs the self-renewal of this subpopulation and results in defective elimination of damaged mitochondria, excessive inflammation, exacerbated cardiac dysfunction, and decreased survival in sepsis. Single-cell RNA-seq, fate mapping, Trem2 KO mouse model of sepsis, mitochondria scavenging assays, intrapericardial cell transfer experiments Nature metabolism High 36635449
2023 TREM2 deficiency restricts the emergence of lipid-associated macrophages (LAMs) and formation of hepatic crown-like structures; TREM2+ macrophages are superior collagen degraders and required for MASH fibrosis regression; TREM2 imparts protection through phagocytosis, lipid handling, and collagen degradation. scRNA-seq of mouse MASH progression/regression, Trem2 KO mice, collagen degradation assays, lipid handling assays PNAS High 39172787
2023 Microglia gravitate toward amyloid plaques through TREM2 recognition of externalized phosphatidylserine (ePtdSer) on dystrophic neurons surrounding Aβ plaques; TREM2 loss-of-function (frameshift mutation in exon 2) organoids show reduced TREM2 levels and impaired phagocytic activity toward ePtdSer-positive Aβ plaques. 2D/3D/4D co-culture systems, brain organoids with TREM2 loss-of-function mutations, CRISPR-Cas9 APOE4 lines, APPNL-G-F/MAPT double knock-in mice, live imaging of microglial migration Advanced science Medium 38981007
2024 TREM2 in macrophages regulates foamy macrophage specification and oxLDL uptake in atherosclerosis; Trem2 loss reduces foamy macrophage ability to take up oxLDL; mechanistically, Trem2-deficient macrophages fail to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival; myeloid-specific Trem2 deletion attenuates plaque progression. Integrated scRNA-seq trajectory analysis, genome-wide CRISPR screen, myeloid-specific Trem2 KO mice, cholesterol efflux assays, oxLDL uptake assays Nature cardiovascular research High 38646596
2024 TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis by inhibiting p38 MAPK phosphorylation and PPARγ phosphorylation, thereby increasing PPARγ nuclear transcriptional activity and promoting CD36 scavenger receptor transcription; TREM2 overexpression in SMCs and macrophages increases CD36-dependent lipid influx. ApoE-/- and Trem2-/-/ApoE-/- double KO mice, TREM2 overexpression in primary cells, Western blot for p38/PPARγ phosphorylation, CD36 promoter activity assays Cellular and molecular life sciences Medium 37133566
2024 TREM2 is essential for efferocytosis capacity of macrophages and survival of lipid-laden macrophages in atherosclerotic lesions; TREM2 deficiency increased necrotic core formation; TREM2 agonism decreased necrotic core formation in early atherosclerosis. Hematopoietic and global TREM2 KO mice in atherosclerosis model, TREM2 agonist treatment, efferocytosis assays, plaque analysis Nature cardiovascular research High 38974464
2024 CNS-enriched sphingolipids bind TREM2 on myeloid cells in GBM and elicit antitumor responses; TREM2 is immunoprotective in GBM (opposite to peripheral cancers), negatively correlating with immunosuppressive signatures; TREM2 deficiency promotes GBM progression, while AAV-mediated TREM2 overexpression impedes GBM progression. Genetic/pharmacological TREM2 deficiency in vivo, scRNA-seq and spatial sequencing, sphingolipid-TREM2 binding assays, AAV-TREM2 overexpression, anti-PD-1 combination therapy Cancer cell High 38788719
2024 TREM2 promotes macrophage metabolic reprogramming after efferocytosis through the SYK-SMAD4 signaling pathway, which decreases SLC25A53 transcription, impairing NAD+ transport into mitochondria and causing a TCA cycle breakpoint that increases itaconate production; secreted itaconate from TREM2+ macrophages inhibits cardiomyocyte apoptosis and promotes fibroblast proliferation after myocardial infarction. RNA-seq, molecular docking, targeted metabolomics (LC-MS), macrophage-specific TREM2 KO mice, in vitro co-culture experiments Cell death and differentiation Medium 38182899
2024 TREM2 deficiency in Schwann cells disrupts glycolytic flux and oxidative metabolism, impairs cell proliferation, triggers mitochondrial damage and autophagy via AMPK activation and impaired PI3K-AKT-mTOR signaling; TREM2 deficiency also impairs energy metabolism and axonal growth in sciatic nerve and exacerbates neurological deficits in a mouse model of acute motor axonal neuropathy. TREM2-deficient Schwann cells, metabolomic analysis, AMPK/PI3K-AKT-mTOR pathway analysis, mouse model of AMAN, nerve regeneration assays Cell death & disease Medium 38453910
2025 TREM2 functions as a key braking mechanism for the NLRP3/NF-κB/IL-1β inflammasome pathway in tumor-associated macrophages; TREM2 depletion combined with microbial LPS triggers IL-1β upregulation and pathogenic inflammation that fuels pancreatic cancer development; IL-1β inhibition or microbiome ablation reverses accelerated PDAC progression caused by TREM2 depletion. KPPC;Trem2-/- transgenic mouse model of spontaneous PDAC, scRNA-seq, IL-1β inhibition, microbiome ablation experiments Gastroenterology High 39956331

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 TREM2 variants in Alzheimer's disease. The New England journal of medicine 2363 23150934
2017 The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 2151 28930663
2015 TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 1386 25728668
2019 Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 1025 31257031
2017 TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell 949 28802038
2020 Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nature medicine 857 31932797
2016 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 715 27477018
2014 TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science translational medicine 637 24990881
2006 Cutting edge: TREM-2 attenuates macrophage activation. Journal of immunology (Baltimore, Md. : 1950) 568 16951310
2018 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron 566 29518356
2020 TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Neuron 556 31902528
2018 TREM2 - a key player in microglial biology and Alzheimer disease. Nature reviews. Neurology 546 30266932
2020 The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell 475 32531244
2018 Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nature reviews. Immunology 457 30140051
2019 Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nature neuroscience 424 30617257
2020 Coupled scRNA-Seq and Intracellular Protein Activity Reveal an Immunosuppressive Role of TREM2 in Cancer. Cell 391 32783915
2018 New insights into the role of TREM2 in Alzheimer's disease. Molecular neurodegeneration 366 30572908
2019 Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-κB pathways in BV2 cells. Molecular immunology 353 31590042
2017 TREM2, Microglia, and Neurodegenerative Diseases. Trends in molecular medicine 338 28442216
2019 TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease. Neuron 295 31301936
2021 Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell reports 274 34686340
2017 TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 269 28077724
2020 Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO molecular medicine 242 32154671
2017 TREM2-Ligand Interactions in Health and Disease. Journal of molecular biology 217 28432014
2018 Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes. International journal of molecular sciences 216 29361745
2023 TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nature immunology 181 37081148
2015 TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. The Journal of experimental medicine 172 25897174
2023 TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma. Journal of hepatology 167 36889359
2020 APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease. Acta neuropathologica 165 32840654
2022 Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH. Journal of hepatology 162 35750138
2021 TREM2, microglia, and Alzheimer's disease. Mechanisms of ageing and development 162 33516818
2023 TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis. Nature metabolism 152 36635449
2022 Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts. Nature communications 151 35933399
2019 A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth. Cell stem cell 148 30930146
2015 TREM2 in CNS homeostasis and neurodegenerative disease. Molecular neurodegeneration 137 26337043
2018 Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut 131 29374630
2023 Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis. Nature cardiovascular research 124 38646596
2018 High-affinity interactions and signal transduction between Aβ oligomers and TREM2. EMBO molecular medicine 120 30341064
2022 Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading. The Journal of experimental medicine 113 36219197
2021 TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nature neuroscience 113 34916658
2016 TREM2 Function in Alzheimer's Disease and Neurodegeneration. ACS chemical neuroscience 110 26854967
2021 AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Science translational medicine 107 34851693
2022 Trem2 deletion enhances tau dispersion and pathology through microglia exosomes. Molecular neurodegeneration 104 36056435
2022 TREM2 macrophages induced by human lipids drive inflammation in acne lesions. Science immunology 103 35867799
2022 Soluble TREM2: Innocent bystander or active player in neurological diseases? Neurobiology of disease 98 35041990
2020 TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms. Gut 97 32907830
2023 TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma. Science advances 90 37172094
2018 TREM2 triggers microglial density and age-related neuronal loss. Glia 87 30548312
2018 Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease. Journal of neuroimmunology 86 29685286
2022 TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron 85 36368315
2024 TREM2 protects from atherosclerosis by limiting necrotic core formation. Nature cardiovascular research 81 38974464
2017 Neuroprotective Effect of TREM-2 in Aging and Alzheimer's Disease Model. Journal of Alzheimer's disease : JAD 78 27662313
2022 Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. The Journal of experimental medicine 77 36107206
2024 TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53. Cell death and differentiation 73 38182899
2024 Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2. Proceedings of the National Academy of Sciences of the United States of America 71 39172787
2024 TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis. International journal of biological sciences 68 38617547
2023 Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development. Immunity 68 38159572
2021 TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation. Nature communications 68 33863908
2023 TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis. Cellular and molecular life sciences : CMLS 65 37133566
2022 TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. Journal of hepatology 63 35750136
2021 Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage. Frontiers in immunology 62 33628208
2020 Function of TREM1 and TREM2 in Liver-Related Diseases. Cells 59 33297569
2023 TREM2: A new player in the tumor microenvironment. Seminars in immunology 58 36989543
2014 TREM-2 promotes macrophage-mediated eradication of Pseudomonas aeruginosa via a PI3K/Akt pathway. Scandinavian journal of immunology 57 24383713
2024 Distinct roles of TREM2 in central nervous system cancers and peripheral cancers. Cancer cell 54 38788719
2014 What happens to microglial TREM2 in Alzheimer's disease: Immunoregulatory turned into immunopathogenic? Neuroscience 54 25281879
2022 Exploring the Impact of TREM2 in Tumor-Associated Macrophages. Vaccines 50 35746551
2024 Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation. Science translational medicine 48 38478630
2007 The enigmatic function of TREM-2 in osteoclastogenesis. Advances in experimental medicine and biology 44 17966394
2021 Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2. Current opinion in neurobiology 43 34689040
2022 LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions. Molecular neurodegeneration 42 35717259
2023 TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection. Glia 40 36625077
2023 The role of TREM2 in Alzheimer's disease: from the perspective of Tau. Frontiers in cell and developmental biology 40 38020891
2022 The therapeutic potential of TREM2 in cancer. Frontiers in oncology 38 36119485
2022 Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology. Cell reports 38 36417868
2024 Microglia, Trem2, and Neurodegeneration. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 37 38769824
2023 TREM2-IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 37 38151703
2017 Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease. Neurobiology of aging 36 28365005
2025 TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies. Molecular neurodegeneration 35 40247363
2024 Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders. Brain : a journal of neurology 35 37740498
2023 TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome medicine 34 36805764
2022 TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats. Neurobiology of disease 34 35781003
2021 Role of TREM2 in Alzheimer's Disease: A Long Road Ahead. Molecular neurobiology 34 34275100
2023 TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques. Nature communications 33 37024448
2022 Does Soluble TREM2 Protect Against Alzheimer's Disease? Frontiers in aging neuroscience 32 35153729
2018 Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease? Expert opinion on therapeutic targets 32 29889572
2015 Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease. Neurogenetics 32 26001891
2024 Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma. Neuro-oncology 31 38237157
2024 Microglia and TREM2. Neuropharmacology 31 38821351
2023 TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain. Science advances 30 37595041
2024 Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 29 38981007
2023 Profiling TREM2 expression in amyotrophic lateral sclerosis. Brain, behavior, and immunity 27 36681358
2023 TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages. Glia 27 37641212
2021 TREM2 expression in the brain and biological fluids in prion diseases. Acta neuropathologica 27 33881612
2020 TMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities. Cell death & disease 27 32826884
2023 TREM2, microglial and ischemic stroke. Journal of neuroimmunology 25 37302170
2025 TREM2 Depletion in Pancreatic Cancer Elicits Pathogenic Inflammation and Accelerates Tumor Progression via Enriching IL-1β+ Macrophages. Gastroenterology 24 39956331
2024 TREM2 deficiency impairs the energy metabolism of Schwann cells and exacerbates peripheral neurological deficits. Cell death & disease 24 38453910
2023 Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology. Molecular neurodegeneration 24 36721205
2023 Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome. Cell reports 24 36800288