TREM-2 Protects the Liver from Immune-Mediated Hepatocellular Damage

Sharif, Omar; Oakley, Fiona; Esparza-Baquer, Aitor; Korosec, Ana; Mann, Jason R.; Labiano, Ibone; Tiniakos, Dina; Gawish, Riem; Jiménez-Agüero, Raúl; Bujanda, Luís; Banales, J.M.; Knapp, S.; Mann, DA

doi:10.1016/s0168-8278(16)00042-8

Cited by 7 publications

(7 citation statements)

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“…Analysis of VAT macrophages in obese mice deficient in TREM2, revealed that its signaling is key for establishment of the LAM phenotype and that LAMs are critical locally for VAT tissue remodeling in obesity (especially establishment of crownlike structures and restraining adipocyte growth) and systemically for limiting obesity-related metabolic derailment (Jaitin et al, 2019). Similar transcriptional signatures were also identified in aortic macrophages during atherosclerosis (Cochain et al, 2018), fatty livers of mice fed a high-fat diet (Jaitin et al, 2019), other models of liver injury (acute and chronic) (Perugorria et al, 2018;Xiong et al, 2019), as well as human liver cirrhosis (Ramachandran et al, 2019). A recent preprint suggested that, in liver injury, TREM2 signaling restrains the inflammatory response and promotes tissue remodeling; e.g., by controlling endothelial phenotypes (Coelho et al, 2019).…”

Section: Llmentioning

confidence: 82%

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Deczkowska

Weiner

Amit

2020

Cell

375

315

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Alzheimer's disease, obesity-related metabolic syndrome, and cancer are the leading causes of death and among the most costly medical conditions in the Western world. In all three cases, recent discoveries establish the TREM2 receptor as a major pathology-induced immune signaling hub that senses tissue damage and activates robust immune remodeling in response to it. In this review, we summarize and question what is known and remains to be discovered about TREM2 signaling pathway, track the consequences of its activation in physiological niches and pathological contexts, and highlight the promising potential of therapeutic manipulation of TREM2 signaling.

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Section: Llmentioning

confidence: 82%

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Deczkowska

Weiner

Amit

2020

Cell

375

315

View full text Add to dashboard Cite

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“…Liver mononuclear cells were isolated as previously described (6,7). Mice were sacrificed and the livers were perfused via the portal vein with HBSS, cut into small pieces and digested for 1 hr at 37°C in RPMI containing 0.05% collagenase/dispase (Roche, #10269638001) and 0.01% trypsin inhibitor (Thermo Fisher Scientific, #17075029).…”

Section: Isolation Of Liver Mononuclear Cellsmentioning

confidence: 99%

Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

Sharif¹,

Brunner²,

Korosec³

et al. 2021

Preprint

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Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated ATM-expressed TREM2 promoted health. Here, we identified that in mice TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in TREM2’s systemic protective effects on metabolic health.

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“…The CCl 4 -induced animal model of acute liver injury is well established, leading to fibrosis, inflammation and apoptotic response in mice ( 6 ). Previous studies have assessed the possible molecular mechanism of liver toxicity induced by CCl 4 ( 7 , 8 ). Certain hepatoprotective agents have been investigated and applied in clinical practice, but a large proportion of them have potential adverse effects ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation

et al. 2018

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Acute liver injury is characterized by fibrosis, inflammation and apoptosis, leading to liver failure, cirrhosis or cancer and affecting the clinical outcome in the long term. However, no effective therapeutic strategy is currently available. Breviscapine, a mixture of flavonoid glycosides, has been reported to have multiple biological functions. The present study aimed to investigate the effects of breviscapine on acute liver injury induced by CCl4 in mice. C57BL/6 mice were subjected to intraperitoneal injection with CCl4 for 8 weeks with or without breviscapine (15 or 30 mg/kg). Mice treated with CCl4 developed acute liver injury, as evidenced by histological analysis, Masson trichrome and Sirius Red staining, accompanied with elevated levels of alanine aminotransferase and aspartate aminotransferase. Furthermore, increases in pro-inflammatory cytokines, chemokines and apoptotic factors, including caspase-3 and poly(ADP ribose) polymerase-2 (PARP-2), were observed. Breviscapine treatment significantly and dose-dependently reduced collagen deposition and the fibrotic area. Inflammatory cytokines were downregulated by breviscapine through inactivating Toll-like receptor 4/nuclear factor-κB signaling pathways. In addition, co-administration of breviscapine with CCl4 decreased the apoptotic response by enhancing B-cell lymphoma-2 (Bcl-2) levels, while reducing Bcl-2-associated X protein, apoptotic protease activating factor 1, caspase-3 and PARP activity. Furthermore, CCl4-induced oxidative stress was blocked by breviscapine through improving anti-oxidants and impeding mitogen-activated protein kinase pathways. The present study highlighted that breviscapine exhibited liver-protective effects against acute hepatic injury induced by CCl4 via suppressing inflammation and apoptosis.

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TREM-2 Protects the Liver from Immune-Mediated Hepatocellular Damage

Cited by 7 publications

References 0 publications

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation

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