Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: The function of TREM2 in various cell types.

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques: Migration

Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: The TREM2 signaling pathway. (A) TREM2 consists of an extracellular domain containing a V-type immunoglobulin-like domain, a transmembrane region, and a short cytoplasmic domain lacking intrinsic signaling motifs. TREM2 functions by forming a heterodimeric complex with the adaptor proteins DAP10 or DAP12. Upon ligand binding, the immunoreceptor tyrosine-based activation motif (ITAM) within DAP12 undergoes tyrosine phosphorylation, which recruits and activates the tyrosine kinase Syk. This subsequently initiates a cascade of downstream signaling events, including the activation of the PI3K/AKT-mTOR pathway, actin remodeling, Ca 2+ mobilization, and the activation of the NF-κB and MAPK signaling pathways. (B) The ITAM motif of DAP12 can also interact with the inhibitory proteins SHIP1, which mediates the degradation of PIP3 to PIP2, thereby attenuating TREM2 signaling. Additionally, CD33 can recruit phosphatases SHP1 or SHP2 to inhibit Syk phosphorylation, providing a cross-regulatory mechanism to suppress TREM2 signaling. (C) Furthermore, TREM2 signaling is modulated by proteolytic processing. The extracellular domain of TREM2 is cleaved by ADAM10/17, releasing soluble TREM2 (sTREM2), while the intracellular domain (ICD) of TREM2 is cleaved by γ-secretase, generating TREM2 ICD. Both processes contribute to the downregulation of TREM2 signaling activity. Image created with BioRender.com .

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques: Ligand Binding Assay, Activation Assay, Phospho-proteomics, Protein-Protein interactions, Activity Assay

Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: The functions of TREM2. (A) The extracellular domain of TREM2 contains a V-type immunoglobulin domain, that allows TREM2 to interact with multiple ligands, including membrane phospholipids, lipoprotein (LDL, HDL, VLDL), lapidated apolipoproteins APOE, Aβ plaque, tau protein, myelin debris, apoptotic body, synaptic materials, bacteria, viruses, and DNA. Upon binding to these ligands, TREM2 activates downstream signaling pathways, ultimately leading to the activation of proteins associated with phagocytosis and the reorganization of the cytoskeleton, thereby enhancing the phagocytic capacity of macrophages for these ligands. This process plays a crucial role in the clearance of pathogens, apoptotic cells, abnormal protein deposits, and the maintenance of tissue homeostasis by macrophages. (B) TREM2-deficient macrophages exhibit reduced lipid uptake, upregulation of Plin2 expression, and downregulation of ABCA1 expression, leading to increased formation of lipid droplets and reduced cholesterol efflux. The increased intracellular cholesterol is subsequently esterified into cholesterol ester by ACAT1. Additionally, TREM2 deficiency impairs energy and anabolic metabolism in macrophages. (C) The TREM2/DAP12 signaling pathway intersects with the CSF1R signaling pathway to promote macrophages survival and proliferation by activating the PI3K/AKT-mTOR and Wnt/β-catenin signaling pathways. (D) After binding to LPS, TREM2 negatively regulates the TLR signaling pathway and downregulates the PI3K/AKT and NF-κB signaling pathways to alleviate inflammatory responses. Furthermore, TREM2 effectively reduces neuroinflammation in Alzheimer’s disease mouse models by inhibiting the JAK2-STAT1/STAT3 signaling pathway. Please note that, upon activation, TREM2 promotes inflammatory responses through downstream NF-κB and MAPK signaling pathways . However, depending on cell type or specific stimulation conditions, TREM2 can also exhibit anti-inflammatory effects. (D) highlights the mechanisms underlying its anti-inflammatory role. Image created with BioRender.com .

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques: Membrane, Bacteria, Binding Assay, Protein-Protein interactions, Activation Assay, Expressing

Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: TREM2 as a marker in immune related diseases. Metabolic syndrome refers to a complex cluster of metabolic disorders that encompasses various diseases, such as obesity, diabetes, atherosclerosis, and fatty liver, that elevate the risk of multiple organ damage, including brain, heart, lung, and liver injuries. TREM2, a receptor that is primarily known for its anti-inflammatory properties, may play a protective role in multiple noncancerous diseases. However, in various cancers, TREM2 promotes tumorigenesis and cancer progression. Notably, TREM2 may exert dual functions in liver injury, hepatocellular carcinoma, glioma, ovarian cancer and melanoma, whereas in acute myeloid leukemia, TREM2 can halt disease progression. Image created with BioRender.com .

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques: Marker, Biomarker Discovery

Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: The effect of TREM2 + macrophages on disease development.

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques: Protein-Protein interactions, Inhibition, Expressing, Binding Assay

Journal: Frontiers in Immunology

Article Title: TREM2 + macrophages: a key role in disease development

doi: 10.3389/fimmu.2025.1550893

Figure Lengend Snippet: Targeting TREM2 as a therapeutic strategy.

Article Snippet: Additionally, AL002, a humanized monoclonal antibody agonist targeting TREM2 developed by Alector, has demonstrated the ability to effectively penetrate the blood-brain barrier, bind to and activate the TREM2 signaling pathway.

Techniques:

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 1 TREM2 deficiency reduces liver tumor burden. (A) C57BL/6 mice were intraperitoneally (i.p.) injected with DEN once (25 mg/kg) starting at two weeks of age, followed by 20 weekly injections of CCl4 (0.5 mL/kg); the mice were subsequently sacrificed at 24 weeks. Liver tissue was collected for H&E staining. Scale bar, 200 μm. (B) Representative graphs of IHC staining for TREM2 in chemically induced murine HCC and paraneoplastic tissues. Scale bar, 50 μm. (C) Hepa 1–6 cells were injected into the livers of wild-type (WT) and Trem2 knockout (Trem2−/−) mice at four weeks of age to establish an ortho topic model of HCC. The mice were sacrificed and analyzed three weeks after injection (n = 5). Scale bar, 1 cm. (D) Statistical analyses of the mouse liver/ body weight ratio. (E) Representative images of IHC staining for cleaved caspase-3 in liver tumors and corresponding statistics showing the percentage of positively stained cells. Scale bar, 200 μm. (F) The subcutaneous HCC model established with WT and Trem2−/−mice (n = 8). Scale bar, 1 cm. (G, H) Statistical analyses of tumor volume (G) and tumor weight (H) in the mice. *P < 0.05, ***P < 0.001

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: Injection, Staining, Immunohistochemistry, Knock-Out

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 2 TREM2 deficiency attenuates tumor growth by modifying CD8+T cells. (A‒C) IHC staining and quantification of CD8α (A), CD4 (B), and FOXP3 (C) expression in orthotopic liver tumors from WT and Trem2 knockout mice (n = 15 tumor areas from five WT mice and n = 12 tumor areas from four Trem2−/− mice). Scale bar, 50 μm. (D) IHC staining and quantification of CD8α in mouse subcutaneous HCC samples (n = 24 tumor areas from eight mice). Scale bar, 50 μm. (E) Subcutaneous tumor models of HCC in WT and Trem2−/− mice were intraperitoneally (i.p.) injected with a CD8 depletion antibody every three days starting on day 3. (F) Tumors were harvested on day 21, and images were obtained (n = 6). Scale bar, 1 cm. (G) Tumor growth curves of the WT and Trem2−/− groups and single mice after depletion of CD8+ T cells. Pool of two experiments (n = 12). (H) Statistical analysis of the tumor weight. ns, not significant; *P < 0.05, ***P < 0.001

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: Immunohistochemistry, Expressing, Knock-Out, Injection

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 3 Trem2 -deficient macrophages show increased chemokine secretion. (A) Heatmap visualization of RNA sequencing data of BMDMs from WT and Trem2−/− mice. (B) Enrichment analysis of KEGG pathways. (C) Gene set enrichment analysis of Gene Ontology biological processes (GO-BPs). (D) Cytokine microarray assay of WT and Trem2−/− BMDM culture supernatants. (E) Quantification plots of differential cytokine levels. (F) Mouse splenocytes were treat ed with the culture supernatant of BMDMs from WT and Trem2−/− mice for 12 h. Cell migration was assessed via a Transwell assay, and the number of mi grating cells was counted under a microscope. (G) IHC of CXCL10 was performed on mouse orthotopic HCC tissues. Scale bar, 50 μm. P < 0.05, ** P < 0.01

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: RNA Sequencing, Microarray, Migration, Transwell Assay, Microscopy

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 4 TREM2 expression is positively correlated with TGF-β1 in HCC. (A) Heatmap of the expression of TREM2 and the indicated genes in the TGF-β fam ily in single cell types of the human liver (GSE115469) derived from the Human Protein Atlas. (B) Correlations between TGFB1 and TREM2 in TCGA-LIHC and GSE14520 cohorts. (C) Kaplan‒Meier curves of the overall survival of patients with high/low expression of TREM2 and TGFB1 in TCGA-LIHC dataset. (D) TGFB1 expression in normal (n = 50) and tumor tissues (n = 371) from TCGA-LIHC dataset. (E) IHC staining and correlation of TREM2 and TGF-β1 levels in a human HCC tissue microarray. Scale bar, 100 μm. (F) Visualization of Smad3 ChIP-seq (GSE72964) peaks around the Trem2 locus in untreated and TGF-β-treated BMDMs. (G) TREM2 expression in human THP-1 cells and mouse BMDMs in the presence of TGF-β (50 ng/mL) and SB431542 (10 nM), a TGF-β receptor kinase inhibitor. (H, I) Representative blots and statistical analysis of TREM2 levels in THP-1 cells and BMDMs in the presence of TGF-β and SB431542 by western blotting. β-actin was used as the internal control. *P < 0.05, ** P < 0.01, ***P < 0.001

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: Expressing, Derivative Assay, Immunohistochemistry, Microarray, ChIP-sequencing, Western Blot, Control

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 5 TREM2+macrophages are associated with glycolysis and PKM2 expression in HCC cells. (A) Hallmark gene set enrichment in TCGA-LIHC (left) and GSE14520 (right) datasets. (B) Changes in the proliferation of Hepa 1–6 cells treated with conditioned medium (CM) form WT and Trem2−/− BMDMs in the presence or absence of 2-DG (2 mM). (C) The levels of PKM2 protein in Hepa 1–6 cells treated with the indicated CM types were assessed via western blotting. (D) Representative images (left) and statistical analysis of PKM2 staining in adjacent nontumor liver tissues and HCC samples (n = 84 pairs). (E) Representative images of TREM2 staining in human HCC samples with different PKM2 levels. Scale bar, 50 μm. (F) Correlation between TREM2 and PKM2 levels in HCC samples (n = 109). ns, not significant; *P < 0.05, ** P < 0.01, ***P < 0.001

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: Expressing, Western Blot, Staining

Journal: Journal of experimental & clinical cancer research : CR

Article Title: TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.

doi: 10.1186/s13046-025-03287-w

Figure Lengend Snippet: Fig. 6 Secretion of IL-1β by TREM2+macrophages increases PKM2 expression and promotes glycolysis in HCC. (A) Differentially expressed genes between WT and Trem2−/− BMDMs according to RNA-sequencing analysis. (B) The intersection of genes upregulated in WT BMDMs compared with Trem2−/− BMDMs, predicted secreted proteins obtained from the Human Protein Atlas (HPA), and curated proteins regulating glycolysis. (C) Correlations between IL1B and TREM2 expression in TCGA-LIHC (left) and GSE14520 (right) datasets. (D) Correlations of IL6 and WNT6 expression with TREM2 expression in TCGA- LIHC and GSE14520 datasets. (E) Secretion of IL-1β in the CM of the indicated BMDMs. (F) PKM2 levels in Hepa 1–6 cells treated with the indicated CM with or without the IL-1R antagonist raleukin (50 ng/mL). (G) Glucose consumption and lactate production in Hepa 1–6 cells treated with the indicated CM types in the presence or absence of raleukin. (H) Schematic diagram of the tumor-promoting role of TREM2+ macrophages in HCC. ns, not significant; *P < 0.05, ***P < 0.001

Article Snippet: The membranes were incubated overnight at 4 °C with primary antibodies against human TREM2 (1:1000, #91068, Cell Signaling Technology), mouse Trem2 (1:1000, AF1729, R&D Systems), PKM2 (1:1000, #4053, Cell Signaling Technology), and β-actin (1:1000, #TA-09, ZSGB-BIO).

Techniques: Expressing, RNA Sequencing

Journal: EMBO Molecular Medicine

Article Title: Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer’s disease

doi: 10.1038/s44321-024-00190-3

Figure Lengend Snippet: Reagents and tools table

Article Snippet: Monoclonal mouse anti-human TREM2 antibody , Santa Cruz Biotechnology; B-3, sc373828.

Techniques: Recombinant, Sequencing, Software