TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms

Esparza-Baquer, Aitor; Labiano, Ibone; Sharif, Omar; Agirre-Lizaso, Aloña; Oakley, Fiona; Rodrigues, Pedro M.; Zhuravleva, Ekaterina; O’Rourke, Colm J.; Hijona, Elizabeth; Jiménez-Agüero, Raúl; Riaño, Ioana; Landa, Aitor; Casta, Adelaida La; Zaki, Marco Y.W.; Munoz‐Garrido, Patricia; Azkargorta, Mikel; Elortza, Félix; Vogel, Andrea; Schabbauer, Gernot; Aspichueta, Patricia; Andersen, Jesper B.; Knapp, Sylvia; Mann, Derek A.; Bujanda, Luís; Bañales, Jesús M.; Perugorria, María J.

doi:10.1136/gutjnl-2019-319227

Cited by 80 publications

(65 citation statements)

References 72 publications

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“…On the contrary, high TREM2 expression levels were significantly associated with tumor type, higher T stage, higher TNM stage, and higher GRADE in LIHC. It has been described in articles that TREM2 is a new type of tumor suppressor gene for liver cancer, and the decreased expression of TREM2 in HCC patients is associated with poor prognosis [25] .the results are consistent. We conclude that high TREM2 expression may can as an independent prognostic factor for KIRP and liver patients.…”

Section: Discussionsupporting

confidence: 52%

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TREM2 is a prognostic biomarker and correlates in immune infiltrates in kidney renal papillary cell carcinoma and liver hepatocellular carcinoma

Xiang¹,

Fang²,

Ding³

et al. 2021

Preprint

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Background: TREM2 was identified as a marker for tumor-associated macrophages (TAMs) and monocytes. However, there is limited information concerning the TREM2 mRNA levels correlated with the outcome and tumor-infiltrating lymphocytes in different cancers.Methods: To explore the expression pattern and prognostic value of TREM2 in pan-cancer, We use multiple databases, including ONCOMINE, PrognoScan, Kaplan-Meier Plotter, GEPIA, and TIMER. we investigated the correlations between TREM1 expression and immune infiltration in cancers, especially kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC)Results: According to the results from Oncomine and TIMER datasets, in a general way, TREM2 mRNA expression is higher in the majority of the tumor and is lower in lung cancer, compared with normal adjacent tissues. A high expression level of TREM2 was beneficial to the survival of LIHC patients. Both in KIRP and LIHC, TREM2 expression levels showed significant positive correlations with infiltrating levels of macrophages and dendritic cells. It also correlated with diverse immune marker sets. We can also find that TREM2 expression was modestly associated with CD8+T cells in KIRP. However, it is related to the Treg in LIHC.Conclusions: TREM2 may be a prognostic marker in the multitudinous tumor. Furthermore, TREM2 may interact with immune infiltration to influence patient survival in cancers like LIHC and KIRP.

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Section: Discussionsupporting

confidence: 52%

“…TREM2 has been confirmed as a marker for tumor-associated macrophages (TAMs) and monocytes [22]. [25] .the results are consistent. We conclude that high TREM2 expression may can as an independent prognostic factor for KIRP and liver patients.…”

Section: Discussionmentioning

confidence: 59%

TREM2 is a prognostic biomarker and correlates in immune infiltrates in kidney renal papillary cell carcinoma and liver hepatocellular carcinoma

Xiang¹,

Fang²,

Ding³

et al. 2021

Preprint

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“…This work revealed that Trem-2 controls the replenishment of liver macrophage populations after acute and chronic hepatotoxic damage and is a critical determinant of swift tissue repair responses conditioning the emergence of endothelial lineage cells during regeneration. Recent reports proposed that lack of Trem-2 expression in non-parenchymal cells contributes to increased fibrosis in Trem-2 KO mice submitted to CCl4 treatment, to increased liver inflammation after acute APAP treatment ( 24 ) and to increased susceptibility to hepatocarcinogenesis ( 33 ). We noted that Trem-2 KO mice did not show significantly higher intensity of liver damage during acute injury (APAP-D1) but showed sustained tissue damage throughout the tissue repair phase (APAP-D3).…”

Section: Discussionmentioning

confidence: 99%

Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage

et al. 2021

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Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2. During tissue recovery, lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.

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“…Another study supports the protective role of TREM2 in hepatocarcinogenesis. TREM2 attenuates inflammation, oxidative stress and Wnt ligand secretion, preventing hepatocyte proliferation and damage [21]. The differing functions of TREM2 in vivo and in vitro may be caused by differences in animals and cell lines [123].…”

Section: Roles Of Trem In Liver Tumorigenesismentioning

confidence: 99%

Function of TREM1 and TREM2 in Liver-Related Diseases

Sun

Feng

Tang

2020

Cells

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TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases.

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TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms

Cited by 80 publications

References 72 publications

TREM2 is a prognostic biomarker and correlates in immune infiltrates in kidney renal papillary cell carcinoma and liver hepatocellular carcinoma

TREM2 is a prognostic biomarker and correlates in immune infiltrates in kidney renal papillary cell carcinoma and liver hepatocellular carcinoma

Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage

Function of TREM1 and TREM2 in Liver-Related Diseases

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