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.

The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques

“…Dyslipidemia is also associated with the increased expression of inflammatory mediator TREM-1 in advanced plaque (Zysset et al 2016). Further, increased TREM-1 expression is associated with unstable plaque and plaque vulnerability.…”

“…Further, increased TREM-1 expression is associated with unstable plaque and plaque vulnerability. This suggests that dyslipidemia enhances the inflammation in plaque through increased surface expression of TREM-1 leading to increased monocytes homing, production of pro-atherogenic or pro-inflammatory cytokines, and foam cell formation, and thus enhanced the plaque vulnerability (Rai et al 2016;Rao et al 2016a;Zysset et al 2016) (Figures 2 and 3). Increased expression of TREM-1 on matured dendritic cells has been correlated with plaque instability (Rai et al 2016), and DCs and activated T cells have been (Figures 2 and 3).…”

“…RAGE is the receptor for not only AGEs, HMGB-1 (Bangert et al 2016), TLRs (Medeiros et al 2014), and TREM-1 (Zysset et al 2016) but also for the calcium binding S100/calgranulin proteins (S100A8, S100A9, and S100A12) (Oesterle and Bowman 2015), and plays a potential role in inflammation-induced atherosclerosis and destabilization of plaque (Figure 3). This suggests that RAGE axis is a mediator for inflammation-induced development and progression of plaque as well as instability.…”

Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice

“…(5,6) The expression and function of TREM-1 has been indicated in various inflammatory diseases, including sepsis, cancer, retinopathy of prematurity (ROP), atherosclerosis, and experimental colitis. (7)(8)(9) Expression of TREM-1 in hepatic stellate cells was proposed as a prognostic factor in hepatitis B-related hepatocellular carcinoma (HCC), and TREM-1-mediated Kupffer cell activation was found in HCC. (10,11) Little is known about the role of TREM-1 in ALD.…”

Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors

“…11 Moreover, recent evidence has linked TREM-1 to several non-infectious acute and chronic inflammatory diseases, including inflammatory bowel diseases, rheumatoid arthritis, psoriasis, atherosclerosis and cancer. [12][13][14] Noteworthy, in non-small cell lung cancer (NSCLC) patients the expression of TREM-1 by tumor-associated macrophages and the increase of the soluble TREM-1 in pleural effusions have been associated with tumor relapse and poor survival. 15 Recently, it has been demonstrated that TREM-1 is induced in dendritic cells undergoing hypoxia.…”