High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress
High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress
复制标题
高迁移率群 B-1 (HMGB-1) 通过诱导内质网应激促进巨噬细胞来源的泡沫细胞凋亡。
DOI：
10.1159/000491970
复制
发表时间：
2018-01-01
影响因子：
--
通讯作者：
Xu, Biao
中科院分区：
文献类型：
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作者：
Wu, Han;Chen, Zheng;Xu, Biao
背景/目标：高迁移率族B-1（HMGB-1）诱导的内质网应激（ERS）与炎症和树突状细胞成熟有关。C/EB-P同源蛋白（CHOP）是ERS和细胞凋亡的重要组成部分，在动脉粥样硬化中起重要作用。然而，关于HMGB-1在泡沫细胞形成中的作用只有很少的信息。因此，研究HMGB-1诱导的ERS/CHOP途径在巨噬细胞源性泡沫细胞的凋亡和形成中的作用。研究方法：在不存在和/或存在HMGB-1、N-乙酰半胱氨酸（NAC，一种抗氧化剂）、胰高血糖素（Gly，一种HMGB-1抑制剂）、衣霉素（TM，一种ERS诱导剂）和4-苯基丁酸（4-PBA，一种ERS抑制剂）的情况下，用氧化低密度脂蛋白（oxLDL）处理RAW 264.7细胞。通过二氢乙锭（DHE）染色检测活性氧（ROS）的产生。油红O染色、细胞内总胆固醇测定和Dil-oxLDL摄取测定评价巨噬细胞中脂质的积聚。流式细胞术和末端脱氧核苷酸转移酶缺口末端标记法（TUNEL）检测细胞凋亡。Western blot检测HMGB-1/ERS/CHOP通路的表达。结果：oxLDL可诱导HMGB 1的移位和分泌，并呈剂量和时间依赖性，NAC可抑制oxLDL诱导的HMGB 1移位和分泌。oxLDL诱导的巨噬细胞中的脂质积聚被Gly减弱的HMGB-1协同促进。此外，TM与oxLDL协同诱导巨噬细胞脂质蓄积和凋亡，而4-PBA可减轻oxLDL诱导的泡沫细胞凋亡。此外，用4-PBA抑制ERS抑制HMGB-1诱导的CHOP表达。结论：OxLDL通过氧化应激刺激巨噬细胞分泌HMGB-1。HMGB-1通过激活ERS/CHOP通路促进巨噬细胞源性泡沫细胞的形成和凋亡。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: High mobility group B-1 (HMGB-1)-induced endoplasmic reticulum stress (ERS) has been implicated in inflammation and dendritic cell maturation. C/EB-Phomologous protein (CHOP) is a vital component of ERS and apoptosis and plays a critical role in atherosclerosis. However, only a little information is available about the role of HMGB-1 in foam cell formation. Thus, the role of HMGB-1-induced ERS/CHOP pathway in apoptosis and formation of macrophage-derived foam cells is investigated. Methods: RAW264.7 cells were treated with oxidized low-density lipoprotein (oxLDL) in the absence and/or presence of HMGB-1, N-acetylcysteine (NAC, an antioxidant), glycyrrhizin (Gly, an HMGB-1 inhibitor), tunicamycin (TM, an ERS inducer), and 4-phenylbutyrate (4-PBA, an ERS inhibitor). Reactive oxygen species (ROS) production was examined by dihydroethidium (DHE) staining. Oil Red O staining, intracellular total cholesterol assay, and Dil-oxLDL uptake assay evaluated the accumulation of lipids in macrophages. Cell apoptosis was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Western blot detected the expression of HMGB-1/ERS/CHOP pathway. Results: oxLDL induced HMGB1 translocation and secretion in a dose- and time-dependent manner, which was inhibited by NAC. oxLDL-induced lipid accumulation in macrophages was promoted synergistically by HMGB-1 that was attenuated by Gly. Moreover, TM synergized with oxLDL induced lipid accumulation and apoptosis of macrophages; however, 4-PBA alleviated the oxLDL-induced apoptotic foam cells. Additionally, the inhibition of ERS with 4-PBA suppressed the expression of HMGB-1-induced CHOP. Conclusions: OxLDL triggered HMGB-1 secretion in macrophages via oxidative stress. Furthermore, HMGB-1 promoted the formation and apoptosis of macrophage-derived foam cells via activation of ERS/CHOP pathway. (C) 2018 The Author(s) Published by S. Karger AG, Basel