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SARS-CoV-2 Coronavirus Spike Protein-Induced Apoptosis, Inflammatory, and Oxidative Stress Responses in THP-1-Like-Macrophages: Potential Role of Angiotensin-Converting Enzyme Inhibitor (Perindopril)
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2021-09-20 , DOI: 10.3389/fimmu.2021.728896
Tlili Barhoumi 1, 2 , Bandar Alghanem 1, 2 , Hayat Shaibah 1, 2 , Fatmah A Mansour 1, 2 , Hassan S Alamri 1, 2 , Maaged A Akiel 1, 2, 3 , Fayhan Alroqi 1, 2, 4 , Mohammad Boudjelal 1, 2
Affiliation  

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process.

Graphical

Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).



中文翻译:

SARS-CoV-2 冠状病毒刺突蛋白诱导的 THP-1 样巨噬细胞凋亡、炎症和氧化应激反应:血管紧张素转换酶抑制剂(培哚普利)的潜在作用

严重急性呼吸系统综合症相关冠状病毒 2 (SARS) 的纯化尖峰 (S) 糖蛋白——冠状病毒——2)冠状病毒用于研究其对THP-1巨噬细胞、外周血单核细胞(PBMC)和HUVEC细胞的影响。S 蛋白通过与血管紧张素转换酶 2 (ACE2) 受体结合,介导 SARS-CoV-2 进入细胞。我们测量了活力、细胞内细胞因子释放、氧化应激、促炎标志物和 THP-1 样巨噬细胞极化。我们观察到 THP-1 巨噬细胞中细胞凋亡、ROS 生成、MCP-1 和细胞内钙表达的增加。S 蛋白的刺激使 THP-1 巨噬细胞向促炎未来极化,TNFα 和 MHC-II M1 样表型标志物增加。用 100 µM 的 ACE 抑制剂培哚普利处理细胞可减少 S 蛋白诱导的细胞凋亡、ROS 和 MHC-II 表达。我们分析了 HUVEC 细胞在暴露于用 S 蛋白刺激的 THP-1 巨噬细胞的条件培养基 (CM) 后的敏感性。CM 诱导内皮细胞凋亡和 MCP-1 表达。培哚普利治疗减少了这些影响。然而,用 S 蛋白直接刺激 HUVEC 细胞后,HIF1α 和 MCP-1 的表达略微增加,ACE 抑制剂处理显着增加。S 蛋白刺激诱导 ROS 生成并通过上调 TNFα 和白细胞介素 (IL)-17 细胞因子表达改变 PBMC 的促有丝分裂反应。培哚普利 (100 µM) 处理降低了这些影响。S 蛋白的蛋白质组学分析刺激了 THP-1 巨噬细胞,有或没有培哚普利 (100 µM) 暴露超过 400 种差异调节的蛋白质。

Graphical

可能至少部分参与 S 蛋白诱导激活炎症标志物(红色窄)和血管紧张素转换酶抑制剂 (ACEi) 调节该过程(绿色窄)的建议途径。

更新日期:2021-09-20
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