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TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.

ABSTRACT: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe-/- mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1-/-Apoe-/- mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation.

SUBMITTER: Zysset D

PROVIDER: S-EPMC5080444 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.

Zysset Daniel D Weber Benjamin B Rihs Silvia S Brasseit Jennifer J Freigang Stefan S Riether Carsten C Banz Yara Y Cerwenka Adelheid A Simillion Cedric C Marques-Vidal Pedro P Ochsenbein Adrian F AF Saurer Leslie L Mueller Christoph C

Nature communications 20161020

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe<sup>-/-</sup> mouse model. TREM-1 strong ...[more]

PMID: 27762264

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Project description:BackgroundEzetimibe, as a cholesterol absorption inhibitor, has been shown protecting against atherosclerosis when combined with statin. However, side by side comparison has not been made to evaluate the beneficial effects of ezetimibe alone versus statin. Herein, the study aimed to test whether ezetimibe alone would exhibit similar effects as statin and the combination therapy would be necessary in a moderate lesion size.Methods and resultsApoE-/- male mice that were fed a saturated-fat supplemented diet were randomly assigned to different therapeutic regimens: vehicle, ezetimibe alone (10 mg/kg/day), atorvastatin (20 mg/kg/day) or combination of ezetimibe and atorvastatin through the drinking water. On 28 days, mice were sacrificed and aorta and sera were collected to analyze the atherosclerotic lesion and blood lipid and cholesterol levels. As a result, ezetimibe alone exerted similar protective effects on atherosclerotic lesion sizes as atorvastatin, which was mediated by lowering serum cholesterol concentrations, inhibiting macrophage accumulation in the lesions and reducing circulatory inflammatory cytokines, such as monocyte chemoattractant protein (MCP-1) and tumor necrosis factor (TNF-α). In contrast to ezetimibe administration, atorvastatin alone attenuated atherosclerotic lesion which is dependent on its anti-inflammation effects. There were no significance differences in lesion areas and serum concentrations of cholesterol, oxidized LDL and inflammatory cytokines between combination therapy and monotherapy (either ezetimibe or atorvastatin). There were significant correlations between the lesion areas and serum concentrations of cholesterol, MCP-1 and TNF-α, respectively. However, there were no significant correlations between the lesion areas and serum concentrations of TGF-β1 and oxLDL.ConclusionsEzetimibe alone played the same protection against a moderate atherosclerotic lesion as atorvastatin, which was associated with lowering serum cholesterol, decreasing circulating inflammatory cytokines, and inhibiting macrophage accumulation in the lesions.

Project description:HIV-infected children and adolescents may be at risk for cardiovascular disease due to chronic inflammation and exacerbation of risk factors. The aim of this study was as follows: 1) compare cardiovascular risk factors, chronic inflammation, and carotid intima-media thickness (IMTc) between the HIV and control groups; 2) determine the association of HIV and antiretroviral (ART) regimens with cardiovascular risk factors, chronic inflammation, and IMTc; and 3) identify variables associated with elevated IMTc. Cross-sectional analysis of 130 children and adolescents, 8-15 years of age, divided into HIV-infected (n = 65) and healthy control (n = 65) participants. Body fat, blood pressure, glycemia, insulin, and glycated hemoglobin, total cholesterol and fractions (LDL-C and HDL-C), triglycerides, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and the IMTc were measured. The results showed HIV-infected children and adolescents had higher levels of glycemia (87.9 vs. 75.9 mg.dL-1, p< 0.001), LDL-c (94.7 vs. 79.5 mg.dL-1, p = 0.010), triglycerides (101.2 vs. 61.6 mg.dL-1, p< 0.001), CRP (1.6 vs. 1.0 mg.L-1, p = 0.007), IL-6 (1.42 vs. 0.01 pg.mL-1, p< 0.001), TNF-α (0.49 vs. 0.01 pg.mL-1, p< 0.001), mean IMTc (0.526 vs. 0.499 mm, p = 0.009), and lower HDL-c (53.7 vs. 69.4 mg.dL-1, p< 0.001) compared to controls. Systolic blood pressure (β = 0.006, p = 0.004) and TNF-α (β = -0.033, p = 0.029) accounted for 16% of IMTc variability in HIV-infected children and adolescents. In patients using protease inhibitors-based ART, male gender (β = -0.186, p = 0.008), trunk body fat (β = -0.011, p = 0.006), glucose (β = 0.005, p = 0.046), and IL-6 (β = 0.017, p = 0.039) accounted for 28% of IMTc variability. HIV-infected children and adolescents may be at risk for premature atherosclerosis due to chronic inflammation and dyslipidemia. Interventions with the potential to improve lipid profile, mitigate inflammation, and reduce cardiovascular risk are needed.

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TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.

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TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.

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