The Role And Mechanism Of Th17 Cell Inflammatory Response In The Development Of Atherosclerotic Plaque

Backgrounds and ObjectivesIt is well known that atherosclerosis is a chronic inflammatory disease that occurs in the artery wall and is initiated primarily in response to deposition of lipid components.The death and disability rate is extremely high,which seriously threatens life of patients and the quality of their life.T helper 17 cells have been identified as a new subset of lymphocytes which are shown to promote atherosclerosis.However,its specific role and mechanism are still unclear.In the present study,we aim to investigate the following study:（1）We aimed to study Th17 cell frequencies and Th17 related cytokines in patients with coronary heart disease.To assess the diagnostic and prognostic value of T helper 17 cell responses in coronary heart disease patients with vulnerable plaque.（2）In previous studies,CD137-CD137L signaling has been shown to be involved in AS.In this study,we focued on the role of exosomes,we aimed to investigate CD137-CD137L signal regulated the exosomes which derived from endothelial cells induced Th17 cell differentiation,and further mediates plaque formation in the progression of atherosclerosis.Methods（1）A total of 185 adults with coronary heart disease and 72 healthy controls were enrolled in the present study.Th17 cell frequencies,matrix metallopeptidase 9（MMP-9）,procollagen typeⅢand procollagen typeⅠwere studied at baseline,and analyzed the correlations among them.All adults assessed left ventricular diastolic function（LVDF）at baseline and the last time follow-up.Followed up the occurrence of the primary endpoint,and analyzed prognostic value of percentage of Th17 cells in patients with coronary heart disease.（2）We treated mouse brain microvascular endothelial cells（MBECs）with agonist anti-CD137 antibody,then exosomes derived from MBECs which have been teaeted were used to investigate the influence of CD137 signaling in atherosclerosis and the percentage of Th17 cells in vivo and vitro.（3）To investigate whether CD137 signaling regulated EC-derived exosomes to improve Th17 cells differentiation through IL-6,we silencing IL-6 and activating CD137 signal in MBECs to regulate the exosomes,and then observed the effect of exosomes derived from MBECs in the development of atherosclerosis and Th17 cell differentiation.MBECs were treated with interleukin（IL）-17 were used to evaluate the effect of IL-17in the function of MBECs.Results（1）The percentage of Th17 cells were increased in patients with coronary heart disease,particularly in adults with vulnerable plaque.Receiver operating characteristic（ROC）analysis demonstrated that the area under the curve of Th17 cell frequencies for predicting of vulnerable plaque was 0.941（95%CI,0.913-0.976;p<0.001）,and the cut-off value was 2.5%.On logistic regression analysis,the percentage of Th17 cells was an independent predictor of vulnerable plaque（odd ratio=1.53,95%CI=1.21-2.29;p=0.004）.The percentage of Th17 cells was significantly correlated with the levels of fibrotic parameters.According to the cut-off value of the percentage of Th17 cells,the patients with a lower level of Th17 cell frequencies had a better LVDF and a lower probability of the primary endpoint.（2）CD137-Exo efficiently induced the percentage of Th17 cells and the development of atherosclerosis in Apo E^-/-mice.The IL-6 contained in CD137-Exo were verified to increase the percentage of Th17 cells in the development of atherosclerosis.CD137-Exo induced Th17 cell differentiation and the progression of atherosclerosis via NF-КB pathway mediated the expression of IL-6.（3）In vitro,recombinant mouse IL-17 protein increased apoptosis in MBECs subjected to inflammation induced by lipopolysaccharide（LPS）.The expression of cleaved-caspase-3 and Bim were increased.The levels of MCP-1,s ICAM-1,and E-selection in the supernatants of MBECs after recombinant mouse IL-17 protein treatment were significantly increased（P<0.05）.Conclusions（1）The percentage of Th17 cells in peripheral blood can be used as an inflammatory biomarker to diagnose vulnerable plaque in patients with coronary heart disease,be used as a predictor to evaluate the improvement of left ventricular diastolic function and the the occurrence of the primary endpoint events in patients with coronary artery disease.（2）CD137-CD137 signal regulated the IL-6 expression of exosomes from endothelial cells which induced Th17 cells differentiation in the development of plaques in atherosclerosis.（3）Vascular endothelial cell inflammation could induce Th17 cell inflammatory responses in circulatory system.The increased of Th17 cell frequencies induced progression of endothelial dysfunction,and amplified the inflammatory responses in local arterial wall,which improved the development of atherosclerotic plaque.