Journal: Journal of neuroinflammation

Article Title: Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration.

doi: 10.1186/s12974-025-03420-8

Figure Lengend Snippet: Fig. 4 TREM2 expression does not alter microglia density (A-C) Representative images of piriform cortical region (A) and quantification (B and C) of microgliosis by immunofluorescence staining with Iba1 anti body. Scale bar, 500 μm. (D-F) Representative images of hippocampus (D) and quantification (E and F) of microgliosis by Iba1 immunofluorescence stain ing. Scale bar, 500 μm. Sample size: n = 19–23 mice/group, with mixed sexes. Each datapoint (circle) represents an individual animal, male and female mice are labeled as solid and open circles, respectively. Data are shown as mean ± SEM. Mann-Whitney tests were used for statistical analysis. P values < 0.05 were considered to be statistically significant. N.S., not significant.

Article Snippet: The following primary antibodies were used: anti-human TREM2 (Cat# 91068, Cell Signaling Technology, 1:1,000), and anti-β-actin (Cat# A2228, Sigma-Aldrich, 1:2,000) antibodies.

Techniques: Expressing, Immunofluorescence, Staining, Labeling, MANN-WHITNEY

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

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 sections were subsequently incubated with antibodies against mouse Trem2 (1:300, ab86491, Abcam), CD8 (1:800, #98941, Cell Signaling Technology), CD4 (1:800, BS6982, Bioworld Technology), FOXP3 (1:800, ab215206, Abcam), cleaved caspase-3 (1:800, #9661, Cell Signaling Technology), TGF-β1 (1:800, ab215715, Abcam), PKM2 (1:1600, #4053, Cell Signaling Technology), and human TREM2 (1:1000, #91068, Cell Signaling Technology) at 4 °C overnight.

Techniques: Expressing, RNA Sequencing

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