Section of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, 3322 North Broad Street, Medical Office Building, room 212, Philadelphia, PA 19140, USA.
Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2113-21. doi: 10.1161/ATVBAHA.112.255471. Epub 2012 Jul 19.
Cholesterol enrichment occurs in vivo when phagocytes ingest retained and aggregated lipoproteins, damaged or senescent cells, and related debris. We previously reported that enrichment of human monocyte/macrophages with unesterified cholesterol (UC) triggers the release of highly procoagulant microvesicles ([MVs], also called microparticles) through induction of apoptosis. We determined whether UC-induced MVs (UCMVs) might transmit endogenous danger signals and, if so, what molecular processes might be responsible for their production, recognition, and detoxification.
Injection of UCMVs into rats provoked extensive leukocyte rolling and adherence to postcapillary venules in vivo. Likewise, exposure of mouse aortic explants or cultured human endothelial cells to UCMVs augmented the adhesion of human monocytes by several fold and increased endothelial cell intercellular adhesion molecule-1 via nuclear factor-κB activation. To explore molecular mechanisms, we found that UC enrichment of human monocytes, in the absence of other stimuli, induced mitochondrial complex II-dependent accumulation of superoxide and peroxides. A subset of these moieties was exported on UCMVs and mediated endothelial activation. Strikingly, aortic explants from mice lacking lectin-like oxidized low-density lipoprotein receptor-1, a pattern-recognition receptor, were essentially unable to respond to UCMVs, whereas simultaneously treated explants from wild-type mice responded robustly by increasing monocyte recruitment. Moreover, high-density lipoprotein and its associated enzyme paraoxonase-1 exerted unexpected roles in the detoxification of UCMVs.
Overall, our study implicates MVs from cholesterol-loaded human cells as novel carriers of danger signals. By promoting maladaptive immunologic and thrombotic responses, these particles may contribute to atherothrombosis and other conditions in vivo.
当吞噬细胞摄取滞留和聚集的脂蛋白、受损或衰老的细胞以及相关碎片时，胆固醇会在体内蓄积。我们之前的研究报告表明，人单核细胞/巨噬细胞内未酯化胆固醇（UC）的蓄积通过诱导细胞凋亡引发高促凝性微囊泡（[MVs]，也称为微颗粒）的释放。我们确定 UC 诱导的 MV（UCMVs）是否可能传递内源性危险信号，如果是，哪些分子过程可能负责其产生、识别和解毒。
将 UCMVs 注射到大鼠体内可引发广泛的白细胞滚动和在后毛细血管静脉中的黏附。同样，暴露于 UCMVs 的小鼠主动脉外植体或培养的人内皮细胞可使人类单核细胞的黏附增加数倍，并通过核因子-κB 激活增加内皮细胞细胞间黏附分子-1。为了探索分子机制，我们发现 UC 对人单核细胞的蓄积，在没有其他刺激的情况下，诱导线粒体复合物 II 依赖性的超氧化物和过氧化物的积累。这些物质的一部分被导出到 UCMVs 上，并介导内皮细胞的激活。引人注目的是，缺乏模式识别受体凝集素样氧化型低密度脂蛋白受体-1 的小鼠的主动脉外植体基本上无法对 UCMVs 产生反应，而同时用野生型小鼠的外植体处理则通过增加单核细胞募集来强烈反应。此外，高密度脂蛋白及其相关酶对氧磷酶-1 在 UCMVs 的解毒中发挥了意想不到的作用。
总的来说，我们的研究表明载有胆固醇的人细胞的 MV 作为危险信号的新型载体。通过促进适应性免疫和血栓形成反应，这些颗粒可能有助于体内动脉粥样硬化和其他疾病的发生。
