The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification.
The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification.
复制标题
DOI：
10.3389/fimmu.2020.575577
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Dimayuga PC
中科院分区：
文献类型：
--
作者：
Chernomordik F;Cercek B;Lio WM;Mihailovic PM;Yano J;Herscovici R;Zhao X;Zhou J;Chyu KY;Shah PK;Dimayuga PC
人阳离子抗菌肽LL-37是银屑病患者的T细胞自身抗原，银屑病患者的心血管事件风险增加。然而，LL-37作为T细胞自身抗原在动脉粥样硬化背景下的作用仍不清楚。本研究的目的是检测急性冠状动脉综合征（ACS）患者中是否存在对LL-37反应的T细胞。此外，使用LL-37小鼠直系同源物mCRAMP免疫的apoE−/−小鼠评估了对LL-37反应的T细胞在动脉粥样硬化中的作用。用LL-37刺激来自ACS患者的外周血单核细胞（PBMC）。来自稳定型冠状动脉疾病（CAD）患者或自我报告的受试者的PBMC作为对照。用流式细胞术分析T细胞记忆应答。用LL-37刺激PBMC可降低对照组和稳定型CAD患者的CD 8+效应T细胞应答，但在ACS患者中则不然，并与程序性细胞死亡蛋白1（PDCD 1）mRNA表达降低相关。对于小鼠研究，供体apoE−/−小鼠用mCRAMP或佐剂免疫作为对照，然后分离T细胞并过继转移到喂食西方饮食的受体apoE−/−小鼠中。在5周后将小鼠安乐死。收集整个动脉和心脏用于分析动脉粥样硬化斑块。收集脾脏进行流式细胞术和mRNA表达分析。apoE−/−小鼠的连续转移实验显示，mCRAMP T细胞受体小鼠的主动脉斑块面积减少了28%（P < 0.05）。56%的佐剂T细胞受体小鼠在动脉粥样硬化斑块中显示钙化，相比之下，mCRAMP T细胞受体小鼠中没有钙化（Fisher精确检验P = 0.003）。与对照相比，来自用mCRAMP免疫的小鼠的T细胞的受体在CD 8 + T细胞中具有增加的IL-10和IFN-γ表达。总之，来自用LL-37刺激的ACS患者的PBMC中的CD 8+效应T细胞应答的持续性表明LL-37反应性T细胞可能参与急性事件。此外，在apoE−/−小鼠中的研究表明，对mCRAMP反应的T细胞在动脉粥样硬化中具有功能活性，并可能参与调节斑块钙化。
The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS). Furthermore, the role of T cells reactive to LL-37 in atherosclerosis was assessed using apoE−/− mice immunized with the LL-37 mouse ortholog, mCRAMP. Peripheral blood mononuclear cells (PBMCs) from patients with ACS were stimulated with LL-37. PBMCs from stable coronary artery disease (CAD) patients or self-reported subjects served as controls. T cell memory responses were analyzed with flow cytometry. Stimulation of PBMCs with LL-37 reduced CD8+ effector T cell responses in controls and patients with stable CAD but not in ACS and was associated with reduced programmed cell death protein 1 (PDCD1) mRNA expression. For the mouse studies, donor apoE−/− mice were immunized with mCRAMP or adjuvant as controls, then T cells were isolated and adoptively transferred into recipient apoE−/− mice fed a Western diet. Recipient mice were euthanized after 5 weeks. Whole aortas and hearts were collected for analysis of atherosclerotic plaques. Spleens were collected for flow cytometric and mRNA expression analysis. Adoptive transfer experiments in apoE−/− mice showed a 28% reduction in aortic plaque area in mCRAMP T cell recipient mice (P < 0.05). Fifty six percent of adjuvant T cell recipient mice showed calcification in atherosclerotic plaques, compared to none in the mCRAMP T cell recipient mice (Fisher’s exact test P = 0.003). Recipients of T cells from mice immunized with mCRAMP had increased IL-10 and IFN-γ expression in CD8+ T cells compared to controls. In conclusion, the persistence of CD8+ effector T cell response in PBMCs from patients with ACS stimulated with LL-37 suggests that LL-37-reactive T cells may be involved in the acute event. Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification.
登录
查看更多内容
影响因子：
--
作者：
Milioti N;Bermudez-Fajardo A;Penichet ML;Oviedo-Orta E
通讯作者：
Oviedo-Orta E
影响因子：
3.7
作者：
Mihailovic PM;Lio WM;Yano J;Zhao X;Zhou J;Chyu KY;Shah PK;Cercek B;Dimayuga PC
通讯作者：
Dimayuga PC
影响因子：
82.9
作者：
Fernandez, Dawn M.;Rahman, Adeeb H.;Giannarelli, Chiara
通讯作者：
Giannarelli, Chiara
影响因子：
6.2
作者：
Cautela, Jennifer;Rouby, Franck;Thuny, Franck
通讯作者：
Thuny, Franck
影响因子：
24
作者：
Grundy, Scott M.;Stone, Neil J.;Wijeysundera, Duminda N.
通讯作者：
Wijeysundera, Duminda N.