Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH

Hendrikx, Tim; Porsch, Florentina; Kiss, Máté G.; Rajcic, Dragana; Papac-Miličević, Nikolina; Hoebinger, Constanze; Göderle, Laura; Hladik, Anastasiya; Shaw, Lisa E.; Horstmann, Hauke; Knapp, Sylvia; Derdak, Sophia; Bilban, Martin; Heintz, Lena; Krawczyk, Marcin; Paternostro, Rafael; Trauner, Michael; Farlik, Matthias; Wolf, Dennis; Binder, Christoph J.

doi:10.1016/j.jhep.2022.06.004

Cited by 89 publications

(98 citation statements)

References 60 publications

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“…Multiple studies have found that Trem2 signaling on adipose macrophages promotes lipid-associated macrophage homeostasis, and whole body Trem2 -/mice have elevated serum cholesterol, increased systemic proinflammatory cytokines, and increased body weight accumulation upon HFD feeding, driven by massive adipocyte hypertrophy 27,61 . Moreover, mice lacking Trem2 have also been found to develop accelerated fatty liver disease and steatohepatitis due to increased inflammation, further emphasizing systemic alterations in this model 28,62 . Interestingly, we report that temporal deletion of Trem2 specifically on macrophages, using the CX3CR1 creER Trem2 flox Ldlr -/model, does not recapitulate the systemic effects seen with whole body Trem2 -/-.…”

Section: Discussionmentioning

confidence: 88%

“…In the periphery, Trem2 has been proposed to regulate homeostatic functions of adipose resident macrophages, and loss of Trem2 resulted in enhanced inflammatory signature and adipose hypertrophy 27 . Similarly, Trem2 expression on liver macrophages has been associated with a reparative phenotype and sTrem2, was proposed as a biomarker for liver disease pathogenesis 28 . Importantly, Trem2 -/- animals have systemic lipid dysregulation and elevated stress hormones, making the total body knockout mouse difficult to interpret for atherosclerosis or chronic inflammation models 27,29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Patterson

Firulyova

et al. 2022

Preprint

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Atherosclerotic plaque formation is driven by the continued expansion of cholesterol loaded foamy macrophages within the arterial intima. Foamy macrophages are primarily derived from newly recruited monocytes, but factors regulating monocyte specification toward foamy macrophage differentiation and prolonged survival in plaque remain poorly understood. We used trajectory analysis of integrated single cell RNA-seq data, along with a genome-wide CRISPR screening approach to identify Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) as a candidate regulator for foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up additional oxidized low density lipoprotein (LDL) cholesterol in vitro. Competitive chimera experiments showed that Trem2-deficient macrophages were less competent to form foamy macrophages when competed against Trem2-sufficient macrophages in vivo. In addition, myeloid specific conditional deletion of Trem2 resulted in a dramatic attenuation of plaque progression, even when targeted in established atherosclerotic lesions. This was independent of changes in circulating inflammatory cytokines, monocyte recruitment, or serum cholesterol levels, but due to a reduction in plaque macrophage proliferation and enhanced cell death. Mechanistically, we link Trem2-deficient macrophages with an inability for cells to sense cholesterol loading and failure to upregulate efflux molecules. Accumulation of cholesterol in the endoplasmic reticulum enhanced activation of the ER-stress response that increased susceptibility for cholesterol-toxicity and cell death in foamy Trem2-deficient macrophages. Overall, this study identifies Trem2 as a regulator of foamy macrophage differentiation, atherosclerotic plaque growth, and as a putative therapeutic target for future intervention studies.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Patterson

Firulyova

et al. 2022

Preprint

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“…Further functional investigation in TREM2-deficient mice will be required to establish the impact of TREM2 in various liver diseases and its suitability as a therapeutic target. As sTREM2 levels were found to be increased in the serum in human and mouse nonalcoholic steatohepatitis 169 , it will also be important to validate specificity and sensitivity of sTREM2 as a diagnostic or prognostic marker.…”

Section: Biology Of Trem2mentioning

confidence: 99%

The biology of TREM receptors

Colonna

2023

Nat Rev Immunol

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Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology.

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“… 32 Moreover, using this multi-centre NAFLD cohort, we benchmarked the performance of SMOC2 against recently proposed single-gene biomarkers of NASH and hepatic fibrosis ( TREM2 , AKR1B10 , MFAP4 , and GDF15 ) and determined predictive performance of gene combinations ( Table S6 ). 32 , [37] , [38] , [39] Patients were grouped into severe NAFLD (NAS ≥4) and mild NAFLD (NAS <4), fibrosis (Kleiner fibrosis grade ≥2) and mild fibrosis (Kleiner fibrosis grade <2), and finally NASH (SAF = 3) and no-NASH (SAF ≤2) ( Table S7 ). We sequenced three male needle biopsies, which was insufficient to determine sex-specific differences in hepatic SMOC2 expression.…”

Section: Resultsmentioning

confidence: 99%