PDF(Pubmed)
Abstract：
Disordered lipid accumulation in the arterial wall is a hallmark of atherosclerosis. Previous studies found that the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor of the immunoglobulin family, is increased in mouse atherosclerotic aortic plaques. However, it remains unknown whether TREM2 plays a role in atherosclerosis. Here we investigated the role of TREM2 in atherosclerosis using ApoE knockout (ApoE-/-) mouse models, primary vascular smooth muscle cells (SMCs), and bone marrow-derived macrophages (BMDMs). In ApoE-/- mice, the density of TREM2-positive foam cells in aortic plaques increased in a time-dependent manner after the mice were fed a high-fat diet (HFD). Compared with ApoE-/- mice, the Trem2-/-/ApoE-/- double-knockout mice showed significantly reduced atherosclerotic lesion size, foam cell number, and lipid burden degree in plaques after HFD feeding. Overexpression of TREM2 in cultured vascular SMCs and macrophages exacerbates lipid influx and foam cell formation by upregulating the expression of the scavenger receptor CD36. Mechanistically, TREM2 inhibits the phosphorylation of p38 mitogen-activated protein kinase and peroxisome proliferator activated-receptor gamma (PPARγ), thereby increasing PPARγ nuclear transcriptional activity and subsequently promoting the transcription of CD36. Our results indicate that TREM2 exacerbates atherosclerosis development by promoting SMC- and macrophage-derived foam cell formation by regulating scavenger receptor CD36 expression. Thus, TREM2 may act as a novel therapeutic target for the treatment of atherosclerosis.
摘要：
动脉壁中脂质的无序积累是动脉粥样硬化的标志。先前的研究发现，在骨髓细胞上表达的触发受体2（TREM2），免疫球蛋白家族的跨膜受体，在小鼠动脉粥样硬化的主动脉斑块中增加。然而,目前尚不清楚TREM2是否在动脉粥样硬化中起作用.在这里，我们使用ApoE敲除（ApoE-/-）小鼠模型研究了TREM2在动脉粥样硬化中的作用，原代血管平滑肌细胞（SMC），和骨髓来源的巨噬细胞（BMDM）。在ApoE-/-小鼠中，高脂饮食(HFD)后,小鼠主动脉斑块中TREM2阳性泡沫细胞的密度呈时间依赖性增加.与ApoE-/-小鼠相比，Trem2-/-/ApoE-/-双基因敲除小鼠显示动脉粥样硬化病变大小显著减小，泡沫细胞数,HFD喂养后斑块的脂质负荷程度。TREM2在培养的血管SMC和巨噬细胞中的过表达通过上调清道夫受体CD36的表达而加剧脂质流入和泡沫细胞形成。机械上,TREM2抑制p38丝裂原激活蛋白激酶和过氧化物酶体增殖物激活受体γ（PPARγ）的磷酸化，从而增加PPARγ核转录活性并随后促进CD36的转录。我们的结果表明，TREM2通过调节清道夫受体CD36表达促进SMC和巨噬细胞衍生的泡沫细胞形成，从而加剧了动脉粥样硬化的发展。因此，TREM2可作为动脉粥样硬化治疗的新型治疗靶点。
