Chen Haisheng, Wu Liying, Diao Kaiyuan, Sheng Yixuan, Chen Xiao, Song Yannan, Jin Qiaoruo, Yang Pingchang, Song Jiangping
Department of Cardiovascular Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology Guangzhou, Guangdong, China.
Research Center of Allergy & Immunology, Shenzhen University School of Medicine Shenzhen, China.
Am J Transl Res. 2020 Oct 15;12(10):6827-6840. eCollection 2020.
The vascular endothelial barrier dysfunction is associated with the pathogenesis of many cardiovascular diseases, such as atherosclerosis (AS). This study aims to identify specific antigen (Ag, in short)-specific polymorphonuclear neutrophils (PMN) in AS patients and to investigate the role of "Ag-specific" PMN activation in causing vascular endothelial barrier dysfunction. In this study, PMNs were isolated from blood samples collected from patients with AS and analyzed with immunological approaches. Human umbilical vein endothelial cells (HUVEC) monolayers were used as a vascular endothelial barrier model. The results showed that "Ag-specific" PMNs were identified in the blood of 50 AS patients. This subset of PMN was featured as the FcγRI and specific IgG (sIgG) complexes on the cell surface; exposure to specific Ags triggered the "Ag-specific" PMNs to release proinflammatory cytokines. PMN-derived cytokine levels in the serum were positively correlated with the serum levels of sIgG in AS patients. Exposure of naive PMNs to sIgG formed FcγRI and sIgG complexes on the surface; this conferred PMNs the property to be recognized and activated by specific Ag. Stimulation of "Ag-specific" PMN activated the mitogen-activated protein kinase and the activities of nuclear factor activated T cells and promoted the gene transcription of tumor necrosis factor-α. Coculture of "Ag-specific" PMNs and HUVEC monolayers in the presence of specific Ag resulted in the HUVEC monolayer barrier dysfunction. In conclusion, "Ag-specific" PMNs were identified in AS patients. Activation of the PMNs compromised vascular endothelial barrier function. Therefore, to regulate the "Ag-specific" PMN's activities may have translational potential in the treatment of AS.
血管内皮屏障功能障碍与许多心血管疾病的发病机制相关，如动脉粥样硬化（AS）。本研究旨在鉴定AS患者中特异性抗原（简称Ag）特异性的多形核中性粒细胞（PMN），并研究“Ag特异性”PMN激活在导致血管内皮屏障功能障碍中的作用。在本研究中，从AS患者采集的血样中分离出PMN，并采用免疫学方法进行分析。用人脐静脉内皮细胞（HUVEC）单层作为血管内皮屏障模型。结果显示，在50例AS患者的血液中鉴定出“Ag特异性”PMN。该亚群PMN的特征是细胞表面存在FcγRI和特异性IgG（sIgG）复合物；暴露于特异性Ag会触发“Ag特异性”PMN释放促炎细胞因子。AS患者血清中PMN衍生的细胞因子水平与sIgG血清水平呈正相关。将未致敏的PMN暴露于sIgG会在表面形成FcγRI和sIgG复合物；这赋予PMN被特异性Ag识别和激活的特性。“Ag特异性”PMN的刺激激活了丝裂原活化蛋白激酶以及核因子活化T细胞的活性，并促进了肿瘤坏死因子-α的基因转录。在存在特异性Ag的情况下，将“Ag特异性”PMN与HUVEC单层共培养会导致HUVEC单层屏障功能障碍。总之，在AS患者中鉴定出了“Ag特异性”PMN。PMN的激活损害了血管内皮屏障功能。因此，调节“Ag特异性”PMN的活性在AS治疗中可能具有转化潜力。
