Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China; Sheng Li OilField Central Hospital, Dong Ying, Shandong Province, China.
Int Immunopharmacol. 2024 Oct 25;140:112844. doi: 10.1016/j.intimp.2024.112844. Epub 2024 Aug 1.
To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs.
Thirty male ApoE mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors.
Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-β were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-β (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-β levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-β levels in the spleen and peripheral blood.
Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.
研究胰高血糖素样肽-1（GLP-1）受体激动剂 Exendin-4 对载脂蛋白 E（ApoE）小鼠骨髓来源抑制性细胞（MDSC）比例的影响，探讨其对血浆和脾脏组织中炎性因子浓度的改变，并评估其与 MDSC 的相关性。
将 30 只雄性 ApoE 小鼠随机分为五组（每组 n=6）：对照组（CON）、模型组（MOD）、Exendin-4 干预组（MOD/Ex-4）、Exendin-9-39 干预组（MOD/Ex-9-39）和 Exendin-4+Exendin-9-39 联合干预组（MOD/Ex-4+Ex-9-39）。经过 4 周的药物干预后，采用油红 O 染色和 H&E 染色观察主动脉斑块的变化。通过流式细胞术检测骨髓和外周血中髓源性抑制细胞（MDSC）的含量。采用酶联免疫吸附试验（ELISA）测定小鼠外周血血浆中炎性因子的浓度，采用实时荧光定量聚合酶链反应（RT-qPCR）定量检测脾脏中炎性因子的表达水平。采用 Pearson 相关性分析评估 MDSC 与炎性因子之间的关系。
MOD 组小鼠体重明显高于 CON 组，差异有统计学意义（P<0.05）。经 Exendin-4 干预后，与 MOD 组相比，体重减轻（P<0.05）。此外，与 MOD 组相比，Exendin-4 治疗可显著减少动脉粥样硬化斑块（P<0.001）。经 Exendin-4 干预后，骨髓中 MDSC 比例高于 MOD 组（P<0.001），外周血中 MDSC 比例明显高于 MOD 组（P<0.05）。进一步研究表明，Exendin-4 可以调节小鼠的脂质水平，降低甘油三酯（TG）（P<0.01）、总胆固醇（TC）（P<0.0001）和低密度脂蛋白胆固醇（LDL-C）（P<0.0001）的浓度，同时增加高密度脂蛋白胆固醇（HDL-C）的浓度（P<0.01）。此外，经 Exendin-4 治疗后，外周血中细胞因子白细胞介素-6（IL-6）的水平明显低于 MOD 组（P<0.0001），而白细胞介素-10（IL-10）和转化生长因子-β（TGF-β）的水平明显高于 MOD 组（P<0.0001）。在脾脏中，白细胞介素-10（IL-10）（P<0.0001）和 TGF-β（P<0.001）的水平明显高于 MOD 组。Pearson 相关性分析显示，外周血 MDSC 比例与脾脏和外周血中白细胞介素-10 和 TGF-β水平呈正相关。此外，骨髓中 MDSC 比例与脾脏和外周血中白细胞介素-10 和 TGF-β水平呈正相关。
Exendin-4 可减轻动脉粥样硬化的严重程度。这一过程可能是通过促进载脂蛋白 E 小鼠骨髓和外周血中髓源性抑制性细胞（MDSC）的分泌，调节体内炎性因子的比例，降低小鼠体重，降低血脂来实现的。
