Affinage

TREML4

Trem-like transcript 4 protein · UniProt Q6UXN2

Length
200 aa
Mass
21.9 kDa
Annotated
2026-04-28
25 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TREML4 is a DAP12-associated activating receptor of the TREM family expressed on macrophages and dendritic cell subsets that functions as a positive regulator of innate immune signaling, myeloid cell differentiation, and inflammatory responses. Its extracellular domain binds late apoptotic and necrotic cells, and it amplifies TLR7 signaling by facilitating MyD88 recruitment to TLR7 and promoting p38-dependent STAT1 phosphorylation, thereby driving type I interferon and inflammatory cytokine production critical for antiviral defense and lupus pathogenesis (PMID:19155473, PMID:25848864). During sepsis, TREML4 regulates calcium homeostasis, ER stress, and apoptotic cell death, and its genetic ablation improves survival; in atherosclerosis, it promotes inflammatory gene programs in macrophages and its deficiency reduces plaque burden in ApoE-deficient mice (PMID:33020659, PMID:32292401). TREML4 also serves as a lineage commitment marker distinguishing Ly6Chi monocytes fated to become Ly6Clo nonclassical monocytes, a transition driven by NOTCH2-DLL1 signaling and dependent on IRF2 (PMID:27264183, PMID:37607223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 High

    Identification of TREML4 as a new TREM family receptor that binds dead cells and signals through DAP12 established its molecular identity as an activating innate immune receptor on specific myeloid cell subsets.

    Evidence Fc-fusion binding assay to apoptotic/necrotic cells, co-immunoprecipitation with DAP12, flow cytometry and immunohistochemistry on splenic macrophages and CD8α+ DCs

    PMID:19155473

    Open questions at the time
    • Ligand(s) on dead cells not molecularly identified
    • Signaling downstream of DAP12 engagement not characterized
    • Function beyond dead-cell recognition unknown
  2. 2011 High

    Knockout mouse studies showed TREML4 is dispensable for dead-cell uptake and cross-presentation by CD8α+ DCs but can serve as an efficient antigen-delivery receptor for T cell priming, defining its non-redundant role in targeted antigen delivery rather than scavenging.

    Evidence Treml4 KO mice, anti-Treml4 antibody–antigen fusion targeting in vivo, T cell priming and tumor challenge experiments

    PMID:22210914

    Open questions at the time
    • Mechanism by which anti-Treml4 targeting enhances antigen presentation not resolved at molecular level
    • Contribution to natural antigen presentation in physiological settings unclear
  3. 2014 Medium

    Localization of TREML4 protein to macrophages within necrotic cores of calcified coronary plaques, together with a cis-eQTL conferring increased coronary calcification risk, linked TREML4 to human atherosclerotic disease.

    Evidence Immunohistochemistry on human coronary arteries, eQTL analysis of rs2803496

    PMID:24975946

    Open questions at the time
    • Causal mechanism connecting TREML4 expression to calcification not established
    • eQTL association not functionally validated by gene perturbation in human cells
  4. 2015 High

    An unbiased shRNA screen and KO validation revealed TREML4 as an essential amplifier of TLR7 signaling by promoting MyD88 recruitment to TLR7 and enabling p38–STAT1 phosphorylation, establishing its central signaling mechanism in type I interferon production and autoimmunity.

    Evidence Genome-scale shRNA screen, Treml4−/− macrophage stimulation, Co-IP of MyD88–TLR7, phospho-blotting, MRL/lpr lupus and influenza models

    PMID:25848864

    Open questions at the time
    • Physical interaction between TREML4 and TLR7 not demonstrated
    • How DAP12 association connects to MyD88 recruitment mechanistically unclear
    • Whether TREML4 amplifies other TLR pathways untested
  5. 2016 Medium

    Prospective sorting demonstrated that TREML4 expression marks a committed Ly6Chi monocyte subset fated to become Ly6Clo nonclassical monocytes, separating it from progenitors that can generate cross-priming monocyte-derived DCs.

    Evidence TREML4+/− monocyte subset sorting, GM-CSF/IL-4 differentiation assays, Zbtb46-GFP reporter mice

    PMID:27264183

    Open questions at the time
    • Whether TREML4 is functionally required for the Ly6Chi-to-Ly6Clo transition or merely a marker not resolved
    • Transcriptional regulation of TREML4 during monocyte commitment not identified
  6. 2020 High

    Two studies expanded TREML4's pathophysiological roles: a CRISPR screen showed TREML4 controls calcium homeostasis, ER stress, and apoptosis during sepsis (with KO mice surviving longer), while double-KO atherosclerosis models showed TREML4 drives inflammatory and lipid-regulatory gene programs in macrophages that promote plaque formation.

    Evidence Whole-genome CRISPR screen with CLP sepsis model, Treml4−/− calcium/ER stress/apoptosis assays; ApoE−/−Treml4−/− atherosclerosis model, transcriptomics, metabolomics

    PMID:32292401 PMID:33020659

    Open questions at the time
    • Direct molecular targets linking TREML4 to calcium flux and ER stress pathways not identified
    • Contribution of TLR7 amplification versus other TREML4 functions to sepsis and atherosclerosis phenotypes not dissected
  7. 2022 Medium

    TREML4 was found to be upregulated on Nr4a1-regulated CD138+ Ly6Clo monocytes that produce exuberant TNFα upon TLR7 stimulation, linking TREML4-high patrolling monocytes to lupus-associated diffuse alveolar hemorrhage.

    Evidence Flow cytometry in pristane-induced lupus, Nr4a1-regulated monocyte genetic tracking, TLR7 stimulation assays

    PMID:36264674

    Open questions at the time
    • Whether Nr4a1 directly regulates Treml4 transcription not shown
    • Functional requirement for TREML4 in hemorrhage pathogenesis not tested by loss-of-function
  8. 2023 Medium

    Two studies further defined TREML4 biology: NOTCH2/DLL1 signaling was shown to drive the Ly6Chi-to-Ly6Clo TREML4+ monocyte transition in an IRF2-dependent manner, while TREML4 knockdown in diabetic keratitis suppressed RIPK3-dependent necroptosis, placing TREML4 upstream of necroptotic cell death.

    Evidence In vitro NOTCH2/DLL1 differentiation assay with conditional KO mice (IRF2, NUR77, BCL6); siRNA knockdown in mouse corneal infection model with RIPK3 inhibitor epistasis

    PMID:37279395 PMID:37607223

    Open questions at the time
    • Whether NOTCH2-IRF2 directly induces Treml4 transcription or acts indirectly not established
    • Direct biochemical link between TREML4 and RIPK3/necroptosis machinery not demonstrated
    • Relevance of TREML4-necroptosis axis beyond corneal infection unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the molecular ligand(s) on dead cells recognized by TREML4, the structural basis of TREML4–DAP12 signaling, the direct physical relationship between TREML4 and TLR7, and whether TREML4 has signaling functions independent of TLR7 amplification.
  • No crystal structure or cryo-EM model of TREML4 or TREML4–DAP12 complex
  • Dead-cell ligand identity unknown
  • No direct TREML4–TLR7 physical interaction demonstrated
  • Human genetic loss-of-function studies absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2
Partners
DAP12MYD88TLR7

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 TREML4 (Treml4) is a new TREM family member whose extracellular domain (fused to human IgG Fc) binds to late apoptotic or necrotic cells. It associates with the adaptor molecule DAP12 (DNAX activation protein 12 kDa) but not DAP10 or FcRγ. It is predominantly expressed on CD8α+ dendritic cells and splenic macrophages (red pulp and marginal metallophilic macrophages). Microarray identification, Fc-fusion protein binding assay to dying cells, new monoclonal antibody detection, co-immunoprecipitation with DAP12, flow cytometry and immunohistochemistry for localization Journal of immunology High 19155473
2011 Treml4 participates in antigen presentation in vivo: antigens (OVA, HIV GAGp24, HER2) engineered into anti-Treml4 monoclonal antibodies were efficiently presented to both CD8+ and CD4+ T cells, and anti-Treml4-GAGp24 induced Th1 responses and anti-tumor immunity. Loss of Treml4 (knockout mice) did not impair uptake of dying cells by CD8α+ DCs or cross-presentation, indicating functional redundancy for dead-cell uptake but a non-redundant role in targeted antigen delivery. Treml4 knockout mouse generation, in vivo antigen targeting with engineered anti-Treml4 antibody-antigen fusions, T cell priming assays, tumor challenge experiments Journal of immunology High 22210914
2015 TREML4 is an essential positive regulator of TLR7 signaling in macrophages. TREML4 deficiency impairs: (1) phosphorylation of STAT1 by p38 MAP kinase downstream of TLR7, and (2) recruitment of the adaptor MyD88 to TLR7. Loss of TREML4 reduces type I interferon production, inflammatory cytokines, and autoantibody production in lupus-prone MRL/lpr mice, and impairs antiviral response to influenza. Genome-scale shRNA screen, Treml4−/− mouse macrophage stimulation assays, phospho-STAT1/p38 western blotting, MyD88–TLR7 co-immunoprecipitation, in vivo lupus and influenza models Nature immunology High 25848864
2014 TREML4 protein localizes to macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease), and co-localizes with areas of microcalcification. rs2803496 acts as a TREML4 cis-eQTL with the minor allele conferring up to 6.5-fold increased relative risk of coronary artery calcification. Immunohistochemistry on human coronary plaques, von Kossa staining, RNA-seq eQTL analysis, integrative genomic/transcriptomic/proteomic strategy American journal of human genetics Medium 24975946
2020 TREML4 regulates multiple aspects of innate immune cell function during polymicrobial sepsis: calcium homeostasis, inflammatory cytokine response, myeloperoxidase activation, endoplasmic reticulum stress response, and apoptotic cell death. Genetic ablation of Treml4 increased survival in both acute and chronic phases of sepsis in mice. Whole-genome CRISPR screen in mice, Treml4−/− mouse cecal ligation and puncture (CLP) sepsis model, calcium flux assays, cytokine measurement, myeloperoxidase activity assay, ER stress markers, apoptosis assays Nature immunology High 33020659
2020 TREML4 expression in human M1 macrophages dysregulates inflammatory pathways related to leukocyte activation, apoptosis, and extracellular matrix degradation. In murine M1 macrophages, Treml4 controls expression of genes related to inflammation and lipid regulation; Treml4 deficiency in ApoE−/− mice reduces plaque burden, lesion complexity, macrophage content, and collagen deposition. In oxLDL-loaded macrophages, Treml4 represses genes related to carbohydrate, ion, and amino acid membrane transport, and its deficiency promotes beneficial iron homeostasis and glucose metabolism. Transcriptome analysis of human and murine macrophages with TREML4 manipulation, ApoE−/−/Treml4−/− double-knockout atherosclerosis model, metabolomic analysis, oxLDL treatment assays Frontiers in immunology High 32292401
2022 In pristane-induced lupus, TremL4 expression on Nr4a1-regulated Ly6Clo patrolling monocytes is regulated by Nr4a1 and is upregulated on novel CD138+ monocytes, which exuberantly produce TNFα in response to TLR7 stimulation. These Nr4a1-regulated Ly6Clo monocytes with high TremL4 expression were associated with diffuse alveolar hemorrhage susceptibility. Flow cytometry, genetic mouse models (Nr4a1-regulated monocyte tracking, pristane treatment), TLR7 stimulation assays, cytokine measurement, annexin-V staining eLife Medium 36264674
2023 In diabetic keratitis, TREML4 is upregulated, and its siRNA-mediated knockdown protected T1DM corneas from Pseudomonas aeruginosa infection by suppressing necroptosis, placing TREML4 in a pathway that promotes RIPK3-dependent necroptotic cell death during bacterial infection. siRNA knockdown of Treml4 in mouse corneal infection model, RIPK3/caspase-8 inhibitor experiments, TUNEL staining, quantitative PCR, immunohistochemistry Investigative ophthalmology & visual science Medium 37279395
2016 TREML4 marks a committed Ly6Chi monocyte subset: Ly6Chi TREML4+ monocytes are committed to differentiate into Ly6Clo TREML4+ monocytes and cannot differentiate into Zbtb46+ monocyte-derived DCs capable of cross-priming, whereas Ly6Chi TREML4− monocytes can differentiate into cross-priming Mo-DCs in response to GM-CSF and IL-4. Cell sorting of TREML4+ vs TREML4− monocyte subsets, in vitro differentiation assays with GM-CSF/IL-4, flow cytometry, Zbtb46-GFP reporter mice Cell reports Medium 27264183
2023 NOTCH2 signaling (via DLL1) induces the transition of Ly6Chi TREML4− monocytes into Ly6Clo TREML4+ monocytes in vitro, and this transition requires IRF2 but can occur independently of NUR77 or BCL6, establishing a transcriptional hierarchy for Ly6Clo monocyte development in which TREML4 marks the mature nonclassical subset. In vitro NOTCH2/DLL1 differentiation assay, conditional knockout mice (BCL6, IRF2, NUR77 deletion from myeloid progenitors), flow cytometry tracking of TREML4 expression Proceedings of the National Academy of Sciences of the United States of America Medium 37607223

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells. Cell reports 169 27264183
2015 The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity. Nature immunology 60 25848864
2020 TREML4 receptor regulates inflammation and innate immune cell death during polymicrobial sepsis. Nature immunology 57 33020659
2013 Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome. Clinica chimica acta; international journal of clinical chemistry 52 23535507
2018 Altered Long Non-Coding RNA Transcriptomic Profiles in Ischemic Stroke. Human gene therapy 49 29284304
2009 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. Journal of immunology (Baltimore, Md. : 1950) 47 19155473
2020 A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients. JCI insight 44 33108347
2011 Treml4, an Ig superfamily member, mediates presentation of several antigens to T cells in vivo, including protective immunity to HER2 protein. Journal of immunology (Baltimore, Md. : 1950) 35 22210914
2016 Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiology of aging 32 27084067
2018 Aberrantly expressed long noncoding RNAs and genes in Parkinson's disease. Neuropsychiatric disease and treatment 29 30538480
2014 Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. American journal of human genetics 25 24975946
2020 TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse. Frontiers in immunology 23 32292401
2022 Peripheral blood transcriptomic clusters uncovered immune phenotypes of asthma. Respiratory research 14 36076228
2022 A novel monocyte differentiation pattern in pristane-induced lupus with diffuse alveolar hemorrhage. eLife 13 36264674
2023 Bcl6, Irf2, and Notch2 promote nonclassical monocyte development. Proceedings of the National Academy of Sciences of the United States of America 12 37607223
2019 TREML4 mRNA Expression and Polymorphisms in Blood Leukocytes are Associated with Atherosclerotic Lesion Extension in Coronary Artery Disease. Scientific reports 8 31076644
2023 Diabetes Exacerbates Pseudomonas aeruginosa Keratitis in Streptozotocin-Induced and db/db Mice via Altering Programmed Cell Death Pathways. Investigative ophthalmology & visual science 6 37279395
2024 Transcriptome of Capsular Contracture around Breast Implants Mimics Allograft Rejection: A Matched Case-Control Study. Plastic and reconstructive surgery 5 39787571
2023 Gentiana Scabra Bge Extract (GSE) Protects Against Alcoholic Liver Disease by Regulating the TLR4/NF-κB Pathway in Mice. Frontiers in bioscience (Landmark edition) 5 38062827
2021 TREML4: a Potential Target for Immunotherapy of Sepsis. Discovery medicine 5 35219349
2020 TLR4: the fall guy in sepsis? Cell stress 5 33336149
2025 The role of the TREM receptor family in cardiovascular diseases: Functions, mechanisms, and therapeutic target. Life sciences 4 40068732
2022 TREML4 polymorphisms increase the mRNA in blood leukocytes in the progression of atherosclerosis. Scientific reports 1 36329152
2026 The TREM Receptor Family in Cardiovascular Diseases: Functions, Mechanisms and Therapeutic Perspectives. International immunopharmacology 0 41539000
2026 Nanoplastics target lung monocytes, disrupting immune dynamics. Journal of hazardous materials 0 41934838