Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
J Mol Med (Berl). 2020 Jul;98(7):973-983. doi: 10.1007/s00109-020-01923-w. Epub 2020 May 25.
Activated macrophages show increased expression of vimentin, an intermediate filament protein. Macrophages secrete vimentin into extracellular space; however, the functions of extracellular vimentin and the process of vimentin secretion are not clearly defined. We found that oxidized low-density lipoproteins (oxLDL) via CD36 induced vimentin secretion in macrophages. We also revealed that extracellular vimentin induced macrophages to release inflammatory cytokines and augmented oxLDL-induced release of TNF-α and IL-6. Extracellular vimentin activated NF-κB signaling via phosphorylation of focal adhesion kinase (p-FAK) and IκB kinase (p-IκK). Extracellular vimentin also amplified the oxLDL-induced p-IκK increase and IκB decrease. Vimentin-induced TNF-α release was not dependent on Dectin-1, which is known to bind vimentin. We measured serum vimentin concentrations and found that patients with atherosclerotic coronary artery disease had higher levels of serum vimentin than normal subjects. Circulating oxLDL and vimentin concentrations showed a high degree of correlation. In mouse experiments, vimentin concentration was higher in the sera of apoE null mice with western diet-induced atherosclerosis than in the sera of chow diet-fed apoE null mice without atherosclerosis. We concluded that vimentin is secreted by oxLDL/CD36 interaction in macrophages and extracellular vimentin promotes macrophage release of pro-inflammatory cytokines. This may contribute to atherosclerotic inflammation and based on our analysis of serum vimentin, we suggest serum vimentin as a predictive marker for atherosclerosis. KEY MESSAGES: OxLDL via CD36 induces secretion of vimentin, a cytoskeletal protein in macrophages. Extracellular vimentin induces macrophages to release proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and this process is mediated by activation of focal adhesion kinase (FAK) and NF-ƙB signaling. Serum concentrations of vimentin in coronary artery disease patients are higher than that in control group. Vimentin concentration is strongly correlated with oxLDL concentration in serum.
活化的巨噬细胞表现出波形蛋白（一种中间丝蛋白）表达增加。巨噬细胞将波形蛋白分泌到细胞外空间；然而，细胞外波形蛋白的功能和波形蛋白分泌的过程尚不清楚。我们发现，通过 CD36 氧化的低密度脂蛋白（oxLDL）诱导巨噬细胞分泌波形蛋白。我们还揭示了细胞外波形蛋白诱导巨噬细胞释放炎症细胞因子，并增强 oxLDL 诱导的 TNF-α和 IL-6 的释放。细胞外波形蛋白通过粘着斑激酶（p-FAK）和 IκB 激酶（p-IκK）的磷酸化激活 NF-κB 信号。细胞外波形蛋白还放大了 oxLDL 诱导的 p-IκK 增加和 IκB 减少。波形蛋白诱导的 TNF-α释放不依赖于 Dectin-1，Dectin-1 已知可结合波形蛋白。我们测量了血清中波形蛋白的浓度，发现动脉粥样硬化性冠心病患者的血清波形蛋白浓度高于正常对照。循环 oxLDL 和波形蛋白浓度之间存在高度相关性。在小鼠实验中，载脂蛋白 E 缺失小鼠给予西方饮食诱导动脉粥样硬化时，其血清中波形蛋白浓度高于未患动脉粥样硬化的载脂蛋白 E 缺失小鼠的血清。我们得出结论，oxLDL/CD36 相互作用诱导巨噬细胞中波形蛋白的分泌，细胞外波形蛋白促进巨噬细胞释放促炎细胞因子。这可能有助于动脉粥样硬化炎症，基于我们对血清波形蛋白的分析，我们建议将血清波形蛋白作为动脉粥样硬化的预测标志物。
