Zhang Linhui, Wang Haixia, Wang Zishan, Xu Jianyi, Wang Mengyuan, Wang Wenxin, He Qiongshan, Yu Yun, Yuan Dongping, Bu Guirong, Qiu Runze, Long Jun
School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Department of Pharmacy, Wuxi Huishan Traditional Chinese Medicine Hospital, Wuxi, Jiangsu, China.
Front Cardiovasc Med. 2024 Dec 20;11:1450898. doi: 10.3389/fcvm.2024.1450898. eCollection 2024.
Cholesterol aggregation in dendritic cells (DCs) triggers an inflammatory response and accelerates the development of atherosclerosis (AS). Resveratrol (RES), a natural compound with anti-inflammatory and cholesterol metabolism regulatory properties, has been shown to influence the maturation and inflammatory functions of DCs. However, its relationship with cholesterol metabolism remains unclear. This study aimed to explore the roles of RES in cholesterol metabolism and inflammatory behaviors of DCs in the context of AS. We analyzed the effect of RES on cholesterol efflux from ApoE bone marrow-derived dendritic cells (BMDCs) using qRT-PCR, Western blot, and cholesterol efflux assays; identified the inflammatory status of RES-treated BMDCs and co-cultured T cells using flow cytometry and ELISA; confirmed the effect of RES on blood lipids, atherosclerotic lesions, cholesterol metabolism, and inflammatory response in high-fat diet and lipopolysaccharide-treated ApoE mice; and explored the potential targets of RES in regulating inflammatory behavior via molecular docking. The results revealed that RES promotes cholesterol efflux, increases the expression of efflux transporter ABCA1, and decreases liver X receptor alpha (LXRα) expression in response to a decrease in intracellular cholesterol in ApoE BMDCs. RES also reduced MHC-II cells and downregulated costimulatory molecule CD80 in BMDCs with decreased IL-6 and increased IL-2 production, and suppressed T-cell activation and modulates IL-22 and IL-10 secretion via BMDCs. Furthermore, we confirmed that RES relieves arterial lesions and regulates blood lipids in ApoE mice. RES demonstrated ABCA1 upregulation and LXRα downregulation effects in the aorta and regulated costimulation molecules and Th17/Treg cytokines in the spleen. Furthermore, RES showed multiple hydrogen bonding and low binding energy with ABCA1, suggesting that ABCA1 is a potential target of RES to modulate the inflammatory properties of BMDCs. Our study demonstrated that RES regulates cholesterol efflux and inflammatory behavior in BMDCs, contributing to the control of AS progression and offering new insights for managing inflammatory diseases.
树突状细胞（DCs）中的胆固醇聚集会引发炎症反应并加速动脉粥样硬化（AS）的发展。白藜芦醇（RES）是一种具有抗炎和胆固醇代谢调节特性的天然化合物，已被证明会影响DCs的成熟和炎症功能。然而，其与胆固醇代谢的关系仍不清楚。本研究旨在探讨RES在AS背景下对DCs胆固醇代谢和炎症行为的作用。我们使用qRT-PCR、蛋白质免疫印迹法和胆固醇外流测定法分析了RES对载脂蛋白E骨髓来源树突状细胞（BMDCs）胆固醇外流的影响；使用流式细胞术和酶联免疫吸附测定法确定了RES处理的BMDCs和共培养T细胞的炎症状态；证实了RES对高脂饮食和脂多糖处理的载脂蛋白E小鼠血脂、动脉粥样硬化病变、胆固醇代谢和炎症反应的影响；并通过分子对接探索了RES调节炎症行为的潜在靶点。结果显示，RES促进胆固醇外流，增加外流转运蛋白ABCA1的表达，并随着载脂蛋白E BMDCs细胞内胆固醇的减少而降低肝X受体α（LXRα）的表达。RES还减少了BMDCs中的MHC-II细胞，下调了共刺激分子CD80，同时降低了IL-6水平并增加了IL-2的产生，并通过BMDCs抑制T细胞活化并调节IL-22和IL-10的分泌。此外，我们证实RES可减轻载脂蛋白E小鼠的动脉病变并调节血脂。RES在主动脉中表现出ABCA1上调和LXRα下调作用，并调节脾脏中的共刺激分子和Th17/Treg细胞因子。此外，RES与ABCA1表现出多个氢键且结合能较低，表明ABCA1是RES调节BMDCs炎症特性的潜在靶点。我们的研究表明，RES调节BMDCs中的胆固醇外流和炎症行为，有助于控制AS进展，并为炎症性疾病的管理提供了新的见解。
