TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation

Labiano, Ibone; Agirre-Lizaso, Aloña; Olaizola, Paula; Echebarria, Anne; Huici-Izagirre, Maider; Olaizola, Irene; Esparza-Baquer, Aitor; Sharif, Omar; Hijona, Elizabeth; Milkiewicz, Piotr; Milkiewicz, Małgorzata; González-Romero, Francisco; Aspichueta, Patricia; Monte, María J.; Marín, José J.G.; Vucur, Mihael; Luedde, Tom; Marzioni, Marco; Mann, Derek A.; Bujanda, Luís; Rodrigues, Pedro M.

doi:10.1016/j.jhep.2022.05.044

Cited by 42 publications

(21 citation statements)

References 37 publications

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“…2 and fig. S10) (19,(28)(29)(30)(31). Deleting Trem2, globally or in a tissue-or celltype manner, would therefore not be expected to phenocopy "Fab5 depletion."…”

Section: Discussionmentioning

confidence: 99%

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

et al. 2023

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Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9 + TREM2 + macrophages that express SPP1 , GPNMB , FABP5 , and CD63 . In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1–induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.

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“…2 and fig. S10) (19,(28)(29)(30)(31). Deleting Trem2, globally or in a tissue-or celltype manner, would therefore not be expected to phenocopy "Fab5 depletion."…”

Section: Discussionmentioning

confidence: 99%

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

et al. 2023

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“…Some of the “phenotypic adaptations” of macrophages, mostly discovered in NAFLD/NASH and related animals models, include the contribution to lipid metabolism and lipotoxicity by KC subsets, 88 the evolution of “lipid-associated macrophages” from monocyte-derived macrophages with high TREM2, osteopontin and CD9 expression 89,90 as well as scar-associated macrophages that had been identified in human liver cirrhosis 91 . Mouse models provided important insights into the functional role of these macrophage subsets; surprisingly, disease-associated macrophage phenotypes such as TREM2 + macrophages—initially thought to be inflammatory/fibrogenic—counteract inflammation in various animal models 92 …”

Section: Concepts Of Inflammation In Chronic Liver Diseasesmentioning

confidence: 99%

Therapeutic modulation of the liver immune microenvironment

2023

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Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy–based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.

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“…Researchers synthesised LCA 3-sulphate (LCA-3-S), which binds to RORγt and selectively suppress Th17 cell differentiation [130]. UDCA has been used in the clinic for many years and has a good curative effect on PSC [131]. It also degrades TGF-β and inhibits the differentiation and activation of Treg cells [132], and UDCA enhances the anti-tumour efficacy of anti-PD-1.…”

Section: Bas-based Therapymentioning

confidence: 99%

Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment

Zhang

Gao

et al. 2023

Immunology

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According to reports, gut microbiota and metabolites regulate the intestinal immune microenvironment. In recent years, an increasing number of studies reported that bile acids (BAs) of intestinal flora origin affect T helper cells and regulatory T cells (Treg cells). Th17 cells play a pro‐inflammatory role and Treg cells usually act in an immunosuppressive role. In this review, we emphatically summarised the influence and corresponding mechanism of different configurations of lithocholic acid (LCA) and deoxycholic acid (DCA) on intestinal Th17 cells, Treg cells and intestinal immune microenvironment. The regulation of BAs receptors G protein‐coupled bile acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune cells and intestinal environment are elaborated. Furthermore, the potential clinical applications above were also concluded in three aspects. The above will help researchers better understand the effects of gut flora on the intestinal immune microenvironment via BAs and contribute to the development of new targeted drugs.

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TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation

Cited by 42 publications

References 37 publications

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

Therapeutic modulation of the liver immune microenvironment

Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment

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