小檗碱通过SPHK2/S1P/ERK5通路对ox-LDL诱导的巨噬细胞胞葬功能障碍的影响

付傲妮; 刘婉婷; 李婧; 杨皓天; 李朝荃; 谢玉鑫; 雷偲; 易光辉

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付傲妮, 刘婉婷, 李婧, 杨皓天, 李朝荃, 谢玉鑫, 雷偲, 易光辉.小檗碱通过SPHK2/S1P/ERK5通路对ox-LDL诱导的巨噬细胞胞葬功能障碍的影响[J].湖南中医药大学学报,2026,46(5):889-897[点击复制]

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小檗碱通过SPHK2/S1P/ERK5通路对ox-LDL诱导的巨噬细胞胞葬功能障碍的影响

付傲妮,刘婉婷,李婧,杨皓天,李朝荃,谢玉鑫,雷偲,易光辉

(南华大学衡阳医学院心血管疾病研究所, 湖南省动脉硬化重点实验室, 湖南动脉硬化疾病国际科技合作基地, 湖南衡阳 421001;南华大学湖南省分子靶向新药研究合作创新中心药物与药理研究所, 湖南衡阳 421001;南华大学衡阳医学院基础医学院, 湖南衡阳 421001)

摘要:

目的探究小檗碱（BBR）对氧化低密度脂蛋白（ox-LDL）诱导的巨噬细胞胞葬功能障碍及炎症反应的作用及机制。方法以ox-LDL诱导人THP-1巨噬细胞胞葬功能障碍为模型。将细胞分为对照组、ox-LDL组、ox-LDL+BBR（5、10、20 μmol/L）组、ox-LDL+BBR+ABC294640组、ox-LDL+BBR+ABC294640+S1P组、ox-LDL+BBR+BIX02189组，ox-LDL组用80 μmol/L ox-LDL处理24 h，其他组用80 μmol/L ox-LDL处理2 h后，根据实验需要加入BBR、SPHK2抑制剂ABC294640（25 μmol/L）、外源性S1P（80 nmol/L）或MEK5抑制剂BIX02189（100 nmol/L）共同孵育24 h。通过荧光实验和流式细胞术检测巨噬细胞胞葬效率；用ELISA检测S1P含量；通过Western blot检测MerTK、AXL、TYRO3、SPHK1/2、MEK5、ERK5和p-ERK5蛋白表达水平。结果与对照组相比，ox-LDL组胞葬效率降低（P<0.01，P<0.001），MerTK、AXL、TYRO3、MEK5、p-ERK5/ERK5、SPHK2蛋白表达水平降低（P<0.01，P<0.001），S1P含量降低（P<0.01）。与ox-LDL组相比，20 μmol/L BBR处理组胞葬效率显著增加（P＜0.01），MerTK、AXL、TYRO3、MEK5、p-ERK5/ERK5、SPHK2蛋白表达水平升高（P＜0.05，P＜0.01）。与ox-LDL+20 μmol/L BBR组相比，加入ABC294640后胞葬效率降低（P＜0.01），MerTK、AXL、TYRO3、MEK5、p-ERK5/ERK5、SPHK2蛋白表达水平下降（P＜0.05，P＜0.01）。与ox-LDL+20 μmol/L BBR+ABC294640组相比，加入S1P后胞葬效率增加（P＜0.01，P＜0.05），MerTK、AXL、TYRO3、MEK5、p-ERK5/ERK5、SPHK2蛋白表达水平升高（P＜0.05，P＜0.01）。与ox-LDL+20 μmol/L BBR组相比，加入BIX02189后胞葬效率降低（P＜0.01），MerTK、AXL、TYRO3、MEK5、p-ERK5/ERK5蛋白表达水平下降（P＜0.05，P＜0.01）。结论 BBR可能通过SPHK2/S1P/ERK5途径发挥作用，减轻ox-LDL诱导的巨噬细胞胞葬功能障碍。

DOI：10.3969/j.issn.1674-070X.2026.05.003

投稿时间：2025-12-11

基金项目:国家自然科学基金项目（81770490）；湖南省科技计划项目（2020JJ4535）。

Effects of berberine on low-density lipoprotein (ox-LDL)-induced efferocytosis dysfunction in macrophages via the SPHK2/S1P/ERK5 pathway

FU Aoni, LIU Wanting, LI Jing, YANG Haotian, LI Chaoquan, XIE Yuxin, LEI Cai, YI Guanghui

(Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China;Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China;School of Basic Medical Sciences, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China)

Abstract:

Objective To investigate the effects and mechanisms of berberine (BBR) on oxidized low-density lipoprotein (ox-LDL)-induced macrophage efferocytosis dysfunction and inflammatory response. Methods Using an ox-LDL-induced efferocytosis dysfunction model in human THP-1-derived macrophages, the cells were divided into the following groups: control, ox-LDL, ox-LDL+BBR (5, 10, 20 μmol/L), ox-LDL+BBR+ABC294640, ox-LDL+BBR+ABC294640+S1P, and ox-LDL+BBR+BIX02189 groups. The ox-LDL group was treated with 80 μmol/L ox-LDL for 24 h. In other groups, cells were pretreated with 80 μmol/L ox-LDL for 2 h, followed by co-incubation for 24 h with BBR, the SPHK2 inhibitor ABC294640 (25 μmol/L), exogenous S1P (80 nmol/L), or the MEK5 inhibitor BIX02189 (100 nmol/L), as required. Macrophage efferocytosis efficiency was assessed using fluorescence microscopy and flow cytometry. S1P levels were measured by ELISA. Protein expression levels of MerTK, AXL, TYRO3, SPHK1/2, MEK5, ERK5, and p-ERK5 were determined by Western blot. Results Compared with the control group, the ox-LDL group exhibited decreased efferocytosis efficiency (P<0.001, P<0.01), reduced protein expression levels of MerTK, AXL, TYRO3, MEK5, p-ERK5/ERK5, and SPHK2 (P<0.01, P<0.001), and decreased S1P levels (P<0.01). Compared with the ox-LDL group, treatment with 20 μmol/L BBR significantly increased efferocytosis efficiency (P<0.01) and elevated protein expression levels of MerTK, AXL, TYRO3, MEK5, p-ERK5/ERK5, and SPHK2 (P<0.05, P<0.01). Compared with the ox-LDL+20 μmol/L BBR group, the addition of ABC294640 decreased efferocytosis efficiency (P<0.01) and reduced protein expression levels of MerTK, AXL, TYRO3, MEK5, p-ERK5/ERK5, and SPHK2 (P<0.05, P<0.01). Compared with the ox-LDL+20 μmol/L BBR+ABC294640 group, the addition of S1P increased efferocytosis efficiency (P<0.01, P<0.05) and elevated protein expression levels of MerTK, AXL, TYRO3, MEK5, p-ERK5/ERK5, and SPHK2 (P<0.05, P<0.01). Compared with the ox-LDL+20 μmol/L BBR group, the addition of BIX02189 decreased efferocytosis efficiency (P<0.01) and reduced protein expression levels of MerTK, AXL, TYRO3, MEK5, and p-ERK5/ERK5 (P<0.05, P<0.01). Conclusion BBR may exert its effects through the SPHK2/S1P/ERK5 pathway to alleviate ox-LDL-induced macrophage efferocytosis dysfunction.

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