{"gene":"TREML4","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2009,"finding":"TREML4 (Trem-like 4) binds to late apoptotic or necrotic (dead) cells via its extracellular domain, as demonstrated by a fusion protein of the TREML4 extracellular domain linked to human IgG Fc. TREML4 associates with the adaptor molecule DAP12 (DNAX activation protein 12 kDa) but not DAP10 or FcRγ. TREML4 protein is predominantly expressed on CD8α+ dendritic cells and splenic macrophages (red pulp and marginal metallophilic macrophages).","method":"Fc-fusion protein binding assay to apoptotic/necrotic cells; co-immunoprecipitation with adaptor molecules; flow cytometry; microarray followed by protein validation with monoclonal antibody","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assay (Fc-fusion binding), co-IP for DAP12 association, flow cytometry for localization; single lab but multiple orthogonal methods","pmids":["19155473"],"is_preprint":false},{"year":2011,"finding":"Loss of Treml4 expression in knockout mice did not impair uptake of dying cells by CD8α+ dendritic cells or cross-presentation of cell-associated antigen to CD8+ T cells, indicating overlapping/redundant function with other receptors in vivo for dead-cell uptake. However, Treml4 is required for antigen presentation in vivo: antigens (OVA, HIV GAGp24, HER2) targeted to Treml4 via anti-Treml4 antibodies were efficiently presented to both CD8+ and CD4+ T cells, and anti-Treml4-GAGp24 induced Th1 responses absent in Treml4 knockout mice.","method":"Knockout mouse model; antibody targeting/delivery of antigens to Treml4 in vivo; T cell priming assays; tumor transplantation model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype, antibody targeting with functional T cell readout; single lab, multiple orthogonal approaches","pmids":["22210914"],"is_preprint":false},{"year":2015,"finding":"TREML4 is an essential positive regulator of TLR7 signaling in macrophages. Macrophages from Treml4-/- mice are hyporesponsive to TLR7 agonists and fail to produce type I interferons due to: (1) impaired phosphorylation of STAT1 by p38 MAPK, and (2) decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced inflammatory cytokines and autoantibodies in MRL/lpr lupus-prone mice and inhibited antiviral immune responses to influenza virus.","method":"Genome-scale shRNA screen; Treml4-/- macrophage functional assays (cytokine production, phospho-STAT1, p38 activity); MyD88-TLR7 co-immunoprecipitation; MRL/lpr mouse model; influenza infection model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-scale screen validated by genetic knockout, multiple molecular readouts (p38/STAT1 phosphorylation, MyD88 recruitment), in vivo disease models; single lab but highly rigorous with multiple orthogonal methods","pmids":["25848864"],"is_preprint":false},{"year":2020,"finding":"TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum (ER) stress response, and apoptotic cell death in innate immune cells during polymicrobial sepsis. Genetic ablation of Treml4 in mice increased overall survival in both acute and chronic phases of sepsis.","method":"Whole-genome CRISPR screen in mice; Treml4-/- mice in cecal ligation and puncture (CLP) sepsis model; calcium homeostasis assays; cytokine measurements; myeloperoxidase activity assay; ER stress markers; apoptosis assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased whole-genome CRISPR screen followed by genetic knockout validation with multiple molecular readouts (calcium, cytokines, MPO, ER stress, apoptosis) and survival endpoints","pmids":["33020659"],"is_preprint":false},{"year":2020,"finding":"TREML4 promotes inflammatory programs in macrophages: in human M1 (inflammatory) macrophages, TREML4 expression dysregulates pathways related to leukocyte activation, apoptosis, and extracellular matrix degradation. In Treml4-deficient Apoe-/- mice, atherosclerotic plaque burden and lesion complexity were reduced (decreased macrophage content and collagen deposition). In oxLDL-loaded macrophages, Treml4 represses genes related to carbohydrate, ion, and amino acid membrane transport, and Treml4 deficiency promotes a beneficial relationship between iron homeostasis and glucose metabolism.","method":"Transcriptome analysis of human M1/M2 macrophages with eQTL genotyping; Treml4-/- Apoe-/- mouse atherosclerosis model; histological lesion scoring; transcriptome analysis of oxLDL-loaded macrophages; metabolomic analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined atherosclerosis phenotype and multiple molecular readouts (transcriptomics, metabolomics); single lab","pmids":["32292401"],"is_preprint":false},{"year":2022,"finding":"In pristane-induced lupus, Nr4a1-regulated Ly6Clo patrolling monocytes expressed elevated TremL4, and this TremL4 expression was regulated by Nr4a1. These TremL4-high monocytes produced exuberant TNFα in response to TLR7 stimulation, consistent with TREML4's role in amplifying TLR7 signaling.","method":"Flow cytometry; pristane mouse model; Nr4a1-/- mice; TLR7 stimulation with cytokine measurement; cell surface marker analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (Nr4a1 knockout) with defined phenotype and functional readout (TNFα production); single lab, two orthogonal methods","pmids":["36264674"],"is_preprint":false},{"year":2023,"finding":"In bacterial keratitis, TREML4 is upregulated in diabetic corneas and promotes necroptosis. Downregulation of TREML4 via siRNA protected T1DM corneas from Pseudomonas aeruginosa infection by suppressing necroptosis.","method":"siRNA knockdown of Treml4 in mouse cornea; quantitative PCR for cytokine and Treml4 expression; TUNEL staining; immunohistochemistry for phospho-caspase-8 and phospho-RIPK3; infection susceptibility assays","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with defined infectious phenotype and necroptosis pathway markers; single lab, single method for TREML4 knockdown","pmids":["37279395"],"is_preprint":false},{"year":2026,"finding":"In sepsis-associated encephalopathy, Treml4 is upregulated in hippocampal microglia and drives microglial activation via the Lyn/Syk/ERK signaling pathway. Knockout or knockdown of Treml4 reversed phosphorylation of Lyn, Syk, and ERK, alleviated hippocampal inflammation and oxidative stress, and protected against memory dysfunction. The Lyn agonist tolimidone reversed the protective effects of Treml4 knockdown in LPS-stimulated BV-2 microglia in vitro.","method":"CLP murine sepsis model; Treml4 knockout mice; Western blotting for Lyn/Syk/ERK phosphorylation; siRNA knockdown in BV-2 cells; Lyn agonist rescue experiment; Morris water maze; immunofluorescence; cytokine/oxidative stress assays","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus in vitro siRNA with pharmacological rescue, multiple signaling readouts; single lab","pmids":["42159801"],"is_preprint":false}],"current_model":"TREML4 is a DAP12-associated TREM-family receptor expressed on myeloid cells (macrophages and dendritic cell subsets) that binds dead/necrotic cells extracellularly and functions intracellularly as a positive amplifier of TLR7 signaling by promoting MyD88 recruitment to TLR7 and p38-mediated STAT1 phosphorylation; it also regulates calcium homeostasis, ER stress, and apoptotic/necroptotic cell death in innate immune cells, and in the CNS drives microglial activation through a Lyn/Syk/ERK signaling axis."},"narrative":{"mechanistic_narrative":"TREML4 is a DAP12-associated TREM-family receptor of myeloid cells that links recognition of dying cells to amplification of innate immune signaling and inflammatory cell-fate programs [PMID:19155473, PMID:25848864]. Its extracellular domain binds late apoptotic and necrotic cells, and it pairs selectively with the adaptor DAP12 rather than DAP10 or FcRγ, with expression concentrated on CD8α+ dendritic cells and splenic macrophages [PMID:19155473]. Although dispensable for dead-cell uptake in vivo, TREML4 is required for productive antigen presentation: antigens delivered to TREML4 are efficiently presented to CD8+ and CD4+ T cells [PMID:22210914]. Mechanistically, TREML4 acts as an essential positive amplifier of TLR7 signaling in macrophages, promoting recruitment of MyD88 to TLR7 and p38 MAPK-dependent STAT1 phosphorylation to drive type I interferon and inflammatory cytokine output; its loss attenuates autoantibody and cytokine responses in lupus-prone mice and blunts antiviral immunity [PMID:25848864, PMID:36264674]. Beyond signaling amplification, TREML4 governs inflammatory cell-fate decisions, regulating calcium homeostasis, ER stress, and apoptotic cell death during sepsis, promoting necroptosis in infected diabetic cornea, and driving atherosclerotic plaque progression in macrophages [PMID:33020659, PMID:37279395, PMID:32292401]. In the CNS, microglial TREML4 propagates neuroinflammation through a Lyn/Syk/ERK signaling axis [PMID:42159801]. Across these settings TREML4 genetic ablation is generally protective, marking it as a pro-inflammatory node rather than a homeostatic restraint.","teleology":[{"year":2009,"claim":"Established TREML4 as a myeloid surface receptor that physically recognizes dead cells and signals through a defined adaptor, framing it as a candidate sensor of cell death.","evidence":"Fc-fusion binding to apoptotic/necrotic cells, co-IP of adaptors, and antibody-based flow cytometry across DC and macrophage subsets","pmids":["19155473"],"confidence":"Medium","gaps":["The molecular ligand on dead cells is not identified","DAP12-dependent downstream signaling output was not demonstrated"]},{"year":2011,"claim":"Resolved the in vivo role question by showing TREML4 is redundant for dead-cell uptake but required for antigen presentation, separating recognition from immunological function.","evidence":"Treml4 knockout mice plus antibody-targeted antigen delivery with CD8+/CD4+ T cell priming readouts and a tumor model","pmids":["22210914"],"confidence":"Medium","gaps":["Mechanism linking TREML4 engagement to enhanced presentation is unresolved","Which DC/macrophage subset mediates the effect in vivo is not pinpointed"]},{"year":2015,"claim":"Defined the core intracellular mechanism: TREML4 amplifies TLR7 signaling by promoting MyD88 recruitment and p38-driven STAT1 phosphorylation, connecting the receptor to type I IFN and autoimmunity.","evidence":"Genome-scale shRNA screen validated in Treml4-/- macrophages with phospho-STAT1/p38 and MyD88-TLR7 co-IP, plus MRL/lpr lupus and influenza models","pmids":["25848864"],"confidence":"High","gaps":["How a surface receptor controls cytosolic MyD88-TLR7 assembly is not structurally defined","Whether DAP12 is required for the TLR7-amplifying function is not established"]},{"year":2020,"claim":"Extended TREML4 function to control of inflammatory cell fate and metabolism, showing it shapes calcium, ER stress, and apoptosis in sepsis and drives atherosclerotic inflammation.","evidence":"Whole-genome CRISPR screen and Treml4-/- mice in CLP sepsis and Apoe-/- atherosclerosis models with transcriptomic, metabolomic, calcium, MPO, ER-stress and apoptosis readouts","pmids":["33020659","32292401"],"confidence":"High","gaps":["Direct receptor-proximal signaling driving ER stress and calcium changes is not mapped","Whether these effects depend on the TLR7 axis is unclear"]},{"year":2022,"claim":"Placed TREML4 in a transcriptional circuit by showing Nr4a1 controls its expression in patrolling monocytes that hyper-respond to TLR7, reinforcing the TLR7-amplification model in autoimmunity.","evidence":"Pristane lupus model with Nr4a1-/- mice, flow cytometry, and TLR7-stimulated TNFα measurement","pmids":["36264674"],"confidence":"Medium","gaps":["Direct Nr4a1 binding to the Treml4 locus is not shown","Causal contribution of TremL4-high monocytes to disease is correlative"]},{"year":2023,"claim":"Implicated TREML4 in necroptotic cell-death control during infection, broadening its cell-fate role beyond apoptosis.","evidence":"siRNA knockdown in diabetic mouse cornea during Pseudomonas keratitis with phospho-RIPK3/caspase-8 markers and infection susceptibility","pmids":["37279395"],"confidence":"Medium","gaps":["Single knockdown method without genetic confirmation in this tissue","Receptor-proximal link to the necroptosis machinery is not defined"]},{"year":2026,"claim":"Identified a distinct CNS signaling output in which microglial TREML4 drives neuroinflammation through Lyn/Syk/ERK, extending its pro-inflammatory role to the brain.","evidence":"CLP sepsis model with Treml4 knockout, BV-2 siRNA knockdown, Lyn-agonist rescue, phospho-Lyn/Syk/ERK Western blots, and behavioral testing","pmids":["42159801"],"confidence":"Medium","gaps":["How TREML4 engages the Lyn/Syk kinase cascade is not defined","Relationship between this axis and the macrophage TLR7/p38 pathway is unknown"]},{"year":null,"claim":"The endogenous ligand on dead cells and how surface ligand engagement is mechanistically transduced into divergent outputs (TLR7-MyD88 amplification, ER-stress/apoptosis, necroptosis, Lyn/Syk/ERK) remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined molecular ligand","No unifying model connecting DAP12 association to the multiple downstream pathways","No structural data on the receptor or its complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":["TYROBP","TLR7","MYD88"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXN2","full_name":"Trem-like transcript 4 protein","aliases":["Triggering receptor expressed on myeloid cells-like protein 4"],"length_aa":200,"mass_kda":21.9,"function":"Positively regulates Toll-like receptor TLR7 signaling in macrophages","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q6UXN2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TREML4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TREML4","total_profiled":1310},"omim":[{"mim_id":"614664","title":"TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS-LIKE PROTEIN 4; TREML4","url":"https://www.omim.org/entry/614664"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"choroid plexus","ntpm":1.9}],"url":"https://www.proteinatlas.org/search/TREML4"},"hgnc":{"alias_symbol":["TLT4"],"prev_symbol":[]},"alphafold":{"accession":"Q6UXN2","domains":[{"cath_id":"2.60.40.10","chopping":"35-132","consensus_level":"high","plddt":96.8682,"start":35,"end":132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXN2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXN2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXN2-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TREML4","jax_strain_url":"https://www.jax.org/strain/search?query=TREML4"},"sequence":{"accession":"Q6UXN2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXN2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXN2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXN2"}},"corpus_meta":[{"pmid":"27264183","id":"PMC_27264183","title":"Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27264183","citation_count":172,"is_preprint":false},{"pmid":"25848864","id":"PMC_25848864","title":"The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity.","date":"2015","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25848864","citation_count":61,"is_preprint":false},{"pmid":"33020659","id":"PMC_33020659","title":"TREML4 receptor regulates inflammation and innate immune cell death during polymicrobial sepsis.","date":"2020","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33020659","citation_count":60,"is_preprint":false},{"pmid":"23535507","id":"PMC_23535507","title":"Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.","date":"2013","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23535507","citation_count":52,"is_preprint":false},{"pmid":"29284304","id":"PMC_29284304","title":"Altered Long Non-Coding RNA Transcriptomic Profiles in Ischemic Stroke.","date":"2018","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29284304","citation_count":50,"is_preprint":false},{"pmid":"19155473","id":"PMC_19155473","title":"A new triggering receptor expressed on myeloid cells (Trem) family member, Trem-like 4, binds to dead cells and is a DNAX activation protein 12-linked marker for subsets of mouse macrophages and dendritic cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19155473","citation_count":48,"is_preprint":false},{"pmid":"33108347","id":"PMC_33108347","title":"A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/33108347","citation_count":45,"is_preprint":false},{"pmid":"22210914","id":"PMC_22210914","title":"Treml4, an Ig superfamily member, mediates presentation of several antigens to T cells in vivo, including protective immunity to HER2 protein.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22210914","citation_count":35,"is_preprint":false},{"pmid":"27084067","id":"PMC_27084067","title":"Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set.","date":"2016","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/27084067","citation_count":32,"is_preprint":false},{"pmid":"30538480","id":"PMC_30538480","title":"Aberrantly expressed long noncoding RNAs and genes in Parkinson's disease.","date":"2018","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/30538480","citation_count":29,"is_preprint":false},{"pmid":"24975946","id":"PMC_24975946","title":"Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24975946","citation_count":26,"is_preprint":false},{"pmid":"32292401","id":"PMC_32292401","title":"TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32292401","citation_count":23,"is_preprint":false},{"pmid":"36076228","id":"PMC_36076228","title":"Peripheral blood transcriptomic clusters uncovered immune phenotypes of asthma.","date":"2022","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/36076228","citation_count":16,"is_preprint":false},{"pmid":"36264674","id":"PMC_36264674","title":"A novel monocyte differentiation pattern in pristane-induced lupus with diffuse alveolar hemorrhage.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36264674","citation_count":13,"is_preprint":false},{"pmid":"37607223","id":"PMC_37607223","title":"Bcl6, Irf2, and Notch2 promote nonclassical monocyte development.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37607223","citation_count":12,"is_preprint":false},{"pmid":"37279395","id":"PMC_37279395","title":"Diabetes Exacerbates Pseudomonas aeruginosa Keratitis in Streptozotocin-Induced and db/db Mice via Altering Programmed Cell Death Pathways.","date":"2023","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/37279395","citation_count":9,"is_preprint":false},{"pmid":"31076644","id":"PMC_31076644","title":"TREML4 mRNA Expression and Polymorphisms in Blood Leukocytes are Associated with Atherosclerotic Lesion Extension in Coronary Artery Disease.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31076644","citation_count":8,"is_preprint":false},{"pmid":"39787571","id":"PMC_39787571","title":"Transcriptome of Capsular Contracture around Breast Implants Mimics Allograft Rejection: A Matched Case-Control Study.","date":"2024","source":"Plastic and reconstructive surgery","url":"https://pubmed.ncbi.nlm.nih.gov/39787571","citation_count":8,"is_preprint":false},{"pmid":"33336149","id":"PMC_33336149","title":"TLR4: the fall guy in sepsis?","date":"2020","source":"Cell stress","url":"https://pubmed.ncbi.nlm.nih.gov/33336149","citation_count":6,"is_preprint":false},{"pmid":"35219349","id":"PMC_35219349","title":"TREML4: a Potential Target for Immunotherapy of Sepsis.","date":"2021","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35219349","citation_count":5,"is_preprint":false},{"pmid":"38062827","id":"PMC_38062827","title":"Gentiana Scabra Bge Extract (GSE) Protects Against Alcoholic Liver Disease by Regulating the TLR4/NF-κB Pathway in Mice.","date":"2023","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/38062827","citation_count":5,"is_preprint":false},{"pmid":"40068732","id":"PMC_40068732","title":"The role of the TREM receptor family in cardiovascular diseases: Functions, mechanisms, and therapeutic target.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40068732","citation_count":4,"is_preprint":false},{"pmid":"36329152","id":"PMC_36329152","title":"TREML4 polymorphisms increase the mRNA in blood leukocytes in the progression of atherosclerosis.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36329152","citation_count":1,"is_preprint":false},{"pmid":"41539000","id":"PMC_41539000","title":"The TREM Receptor Family in Cardiovascular Diseases: Functions, Mechanisms and Therapeutic Perspectives.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41539000","citation_count":1,"is_preprint":false},{"pmid":"42159801","id":"PMC_42159801","title":"Treml4 Drives Microglial Activation via the Lyn/Syk/ERK Pathway in Sepsis-Associated Encephalopathy.","date":"2026","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/42159801","citation_count":0,"is_preprint":false},{"pmid":"41934838","id":"PMC_41934838","title":"Nanoplastics target lung monocytes, disrupting immune dynamics.","date":"2026","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/41934838","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15655,"output_tokens":2596,"usd":0.042952,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9777,"output_tokens":2878,"usd":0.060417,"stage2_stop_reason":"end_turn"},"total_usd":0.103369,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"TREML4 (Trem-like 4) binds to late apoptotic or necrotic (dead) cells via its extracellular domain, as demonstrated by a fusion protein of the TREML4 extracellular domain linked to human IgG Fc. TREML4 associates with the adaptor molecule DAP12 (DNAX activation protein 12 kDa) but not DAP10 or FcRγ. TREML4 protein is predominantly expressed on CD8α+ dendritic cells and splenic macrophages (red pulp and marginal metallophilic macrophages).\",\n      \"method\": \"Fc-fusion protein binding assay to apoptotic/necrotic cells; co-immunoprecipitation with adaptor molecules; flow cytometry; microarray followed by protein validation with monoclonal antibody\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assay (Fc-fusion binding), co-IP for DAP12 association, flow cytometry for localization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19155473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of Treml4 expression in knockout mice did not impair uptake of dying cells by CD8α+ dendritic cells or cross-presentation of cell-associated antigen to CD8+ T cells, indicating overlapping/redundant function with other receptors in vivo for dead-cell uptake. However, Treml4 is required for antigen presentation in vivo: antigens (OVA, HIV GAGp24, HER2) targeted to Treml4 via anti-Treml4 antibodies were efficiently presented to both CD8+ and CD4+ T cells, and anti-Treml4-GAGp24 induced Th1 responses absent in Treml4 knockout mice.\",\n      \"method\": \"Knockout mouse model; antibody targeting/delivery of antigens to Treml4 in vivo; T cell priming assays; tumor transplantation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype, antibody targeting with functional T cell readout; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"22210914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TREML4 is an essential positive regulator of TLR7 signaling in macrophages. Macrophages from Treml4-/- mice are hyporesponsive to TLR7 agonists and fail to produce type I interferons due to: (1) impaired phosphorylation of STAT1 by p38 MAPK, and (2) decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced inflammatory cytokines and autoantibodies in MRL/lpr lupus-prone mice and inhibited antiviral immune responses to influenza virus.\",\n      \"method\": \"Genome-scale shRNA screen; Treml4-/- macrophage functional assays (cytokine production, phospho-STAT1, p38 activity); MyD88-TLR7 co-immunoprecipitation; MRL/lpr mouse model; influenza infection model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-scale screen validated by genetic knockout, multiple molecular readouts (p38/STAT1 phosphorylation, MyD88 recruitment), in vivo disease models; single lab but highly rigorous with multiple orthogonal methods\",\n      \"pmids\": [\"25848864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum (ER) stress response, and apoptotic cell death in innate immune cells during polymicrobial sepsis. Genetic ablation of Treml4 in mice increased overall survival in both acute and chronic phases of sepsis.\",\n      \"method\": \"Whole-genome CRISPR screen in mice; Treml4-/- mice in cecal ligation and puncture (CLP) sepsis model; calcium homeostasis assays; cytokine measurements; myeloperoxidase activity assay; ER stress markers; apoptosis assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased whole-genome CRISPR screen followed by genetic knockout validation with multiple molecular readouts (calcium, cytokines, MPO, ER stress, apoptosis) and survival endpoints\",\n      \"pmids\": [\"33020659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TREML4 promotes inflammatory programs in macrophages: in human M1 (inflammatory) macrophages, TREML4 expression dysregulates pathways related to leukocyte activation, apoptosis, and extracellular matrix degradation. In Treml4-deficient Apoe-/- mice, atherosclerotic plaque burden and lesion complexity were reduced (decreased macrophage content and collagen deposition). In oxLDL-loaded macrophages, Treml4 represses genes related to carbohydrate, ion, and amino acid membrane transport, and Treml4 deficiency promotes a beneficial relationship between iron homeostasis and glucose metabolism.\",\n      \"method\": \"Transcriptome analysis of human M1/M2 macrophages with eQTL genotyping; Treml4-/- Apoe-/- mouse atherosclerosis model; histological lesion scoring; transcriptome analysis of oxLDL-loaded macrophages; metabolomic analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined atherosclerosis phenotype and multiple molecular readouts (transcriptomics, metabolomics); single lab\",\n      \"pmids\": [\"32292401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pristane-induced lupus, Nr4a1-regulated Ly6Clo patrolling monocytes expressed elevated TremL4, and this TremL4 expression was regulated by Nr4a1. These TremL4-high monocytes produced exuberant TNFα in response to TLR7 stimulation, consistent with TREML4's role in amplifying TLR7 signaling.\",\n      \"method\": \"Flow cytometry; pristane mouse model; Nr4a1-/- mice; TLR7 stimulation with cytokine measurement; cell surface marker analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (Nr4a1 knockout) with defined phenotype and functional readout (TNFα production); single lab, two orthogonal methods\",\n      \"pmids\": [\"36264674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In bacterial keratitis, TREML4 is upregulated in diabetic corneas and promotes necroptosis. Downregulation of TREML4 via siRNA protected T1DM corneas from Pseudomonas aeruginosa infection by suppressing necroptosis.\",\n      \"method\": \"siRNA knockdown of Treml4 in mouse cornea; quantitative PCR for cytokine and Treml4 expression; TUNEL staining; immunohistochemistry for phospho-caspase-8 and phospho-RIPK3; infection susceptibility assays\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with defined infectious phenotype and necroptosis pathway markers; single lab, single method for TREML4 knockdown\",\n      \"pmids\": [\"37279395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In sepsis-associated encephalopathy, Treml4 is upregulated in hippocampal microglia and drives microglial activation via the Lyn/Syk/ERK signaling pathway. Knockout or knockdown of Treml4 reversed phosphorylation of Lyn, Syk, and ERK, alleviated hippocampal inflammation and oxidative stress, and protected against memory dysfunction. The Lyn agonist tolimidone reversed the protective effects of Treml4 knockdown in LPS-stimulated BV-2 microglia in vitro.\",\n      \"method\": \"CLP murine sepsis model; Treml4 knockout mice; Western blotting for Lyn/Syk/ERK phosphorylation; siRNA knockdown in BV-2 cells; Lyn agonist rescue experiment; Morris water maze; immunofluorescence; cytokine/oxidative stress assays\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus in vitro siRNA with pharmacological rescue, multiple signaling readouts; single lab\",\n      \"pmids\": [\"42159801\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TREML4 is a DAP12-associated TREM-family receptor expressed on myeloid cells (macrophages and dendritic cell subsets) that binds dead/necrotic cells extracellularly and functions intracellularly as a positive amplifier of TLR7 signaling by promoting MyD88 recruitment to TLR7 and p38-mediated STAT1 phosphorylation; it also regulates calcium homeostasis, ER stress, and apoptotic/necroptotic cell death in innate immune cells, and in the CNS drives microglial activation through a Lyn/Syk/ERK signaling axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TREML4 is a DAP12-associated TREM-family receptor of myeloid cells that links recognition of dying cells to amplification of innate immune signaling and inflammatory cell-fate programs [#0, #2]. Its extracellular domain binds late apoptotic and necrotic cells, and it pairs selectively with the adaptor DAP12 rather than DAP10 or FcRγ, with expression concentrated on CD8α+ dendritic cells and splenic macrophages [#0]. Although dispensable for dead-cell uptake in vivo, TREML4 is required for productive antigen presentation: antigens delivered to TREML4 are efficiently presented to CD8+ and CD4+ T cells [#1]. Mechanistically, TREML4 acts as an essential positive amplifier of TLR7 signaling in macrophages, promoting recruitment of MyD88 to TLR7 and p38 MAPK-dependent STAT1 phosphorylation to drive type I interferon and inflammatory cytokine output; its loss attenuates autoantibody and cytokine responses in lupus-prone mice and blunts antiviral immunity [#2, #5]. Beyond signaling amplification, TREML4 governs inflammatory cell-fate decisions, regulating calcium homeostasis, ER stress, and apoptotic cell death during sepsis, promoting necroptosis in infected diabetic cornea, and driving atherosclerotic plaque progression in macrophages [#3, #6, #4]. In the CNS, microglial TREML4 propagates neuroinflammation through a Lyn/Syk/ERK signaling axis [#7]. Across these settings TREML4 genetic ablation is generally protective, marking it as a pro-inflammatory node rather than a homeostatic restraint.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established TREML4 as a myeloid surface receptor that physically recognizes dead cells and signals through a defined adaptor, framing it as a candidate sensor of cell death.\",\n      \"evidence\": \"Fc-fusion binding to apoptotic/necrotic cells, co-IP of adaptors, and antibody-based flow cytometry across DC and macrophage subsets\",\n      \"pmids\": [\"19155473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular ligand on dead cells is not identified\", \"DAP12-dependent downstream signaling output was not demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the in vivo role question by showing TREML4 is redundant for dead-cell uptake but required for antigen presentation, separating recognition from immunological function.\",\n      \"evidence\": \"Treml4 knockout mice plus antibody-targeted antigen delivery with CD8+/CD4+ T cell priming readouts and a tumor model\",\n      \"pmids\": [\"22210914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TREML4 engagement to enhanced presentation is unresolved\", \"Which DC/macrophage subset mediates the effect in vivo is not pinpointed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the core intracellular mechanism: TREML4 amplifies TLR7 signaling by promoting MyD88 recruitment and p38-driven STAT1 phosphorylation, connecting the receptor to type I IFN and autoimmunity.\",\n      \"evidence\": \"Genome-scale shRNA screen validated in Treml4-/- macrophages with phospho-STAT1/p38 and MyD88-TLR7 co-IP, plus MRL/lpr lupus and influenza models\",\n      \"pmids\": [\"25848864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a surface receptor controls cytosolic MyD88-TLR7 assembly is not structurally defined\", \"Whether DAP12 is required for the TLR7-amplifying function is not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended TREML4 function to control of inflammatory cell fate and metabolism, showing it shapes calcium, ER stress, and apoptosis in sepsis and drives atherosclerotic inflammation.\",\n      \"evidence\": \"Whole-genome CRISPR screen and Treml4-/- mice in CLP sepsis and Apoe-/- atherosclerosis models with transcriptomic, metabolomic, calcium, MPO, ER-stress and apoptosis readouts\",\n      \"pmids\": [\"33020659\", \"32292401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor-proximal signaling driving ER stress and calcium changes is not mapped\", \"Whether these effects depend on the TLR7 axis is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TREML4 in a transcriptional circuit by showing Nr4a1 controls its expression in patrolling monocytes that hyper-respond to TLR7, reinforcing the TLR7-amplification model in autoimmunity.\",\n      \"evidence\": \"Pristane lupus model with Nr4a1-/- mice, flow cytometry, and TLR7-stimulated TNFα measurement\",\n      \"pmids\": [\"36264674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Nr4a1 binding to the Treml4 locus is not shown\", \"Causal contribution of TremL4-high monocytes to disease is correlative\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated TREML4 in necroptotic cell-death control during infection, broadening its cell-fate role beyond apoptosis.\",\n      \"evidence\": \"siRNA knockdown in diabetic mouse cornea during Pseudomonas keratitis with phospho-RIPK3/caspase-8 markers and infection susceptibility\",\n      \"pmids\": [\"37279395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single knockdown method without genetic confirmation in this tissue\", \"Receptor-proximal link to the necroptosis machinery is not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a distinct CNS signaling output in which microglial TREML4 drives neuroinflammation through Lyn/Syk/ERK, extending its pro-inflammatory role to the brain.\",\n      \"evidence\": \"CLP sepsis model with Treml4 knockout, BV-2 siRNA knockdown, Lyn-agonist rescue, phospho-Lyn/Syk/ERK Western blots, and behavioral testing\",\n      \"pmids\": [\"42159801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TREML4 engages the Lyn/Syk kinase cascade is not defined\", \"Relationship between this axis and the macrophage TLR7/p38 pathway is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous ligand on dead cells and how surface ligand engagement is mechanistically transduced into divergent outputs (TLR7-MyD88 amplification, ER-stress/apoptosis, necroptosis, Lyn/Syk/ERK) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined molecular ligand\", \"No unifying model connecting DAP12 association to the multiple downstream pathways\", \"No structural data on the receptor or its complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TYROBP\", \"TLR7\", \"MYD88\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}