Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content
Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content
复制标题
DOI：
10.1093/cvr/cvx181
复制
发表时间：
2018-01-01
影响因子：
10.8
通讯作者：
Wahren-Herlenius, Marie
中科院分区：
文献类型：
--
作者：
Brauner, Susanna;Jiang, Xintong;Wahren-Herlenius, Marie
高脂血症患者存在动脉粥样硬化的风险，但并非所有患者都发生心血管疾病，这突出了其他危险因素（如炎症）的重要性。免疫系统的先天性和适应性臂都被认为是斑块形成的起始和传播。三分基序（TRIM）21是组织炎症和促炎细胞因子产生的调节剂，并且与慢性炎性疾病有关。在这里，我们调查了一个潜在的作用TRIM 21在冠状动脉diseases.Methods和结果Trim 21缺陷或野生型骨髓移植到Ldlr（-/-）小鼠喂养高胆固醇饮食。与移植野生型细胞的小鼠相比，Trim 21（-/-）->Ldlr（-/-）小鼠形成了更大的动脉粥样硬化斑块，胶原蛋白含量显著更高。动脉粥样硬化的高胶原蛋白含量正在稳定，并且最近与IL-17有关。有趣的是，Trim 21（-/-）-> Ldlr（-/-）小鼠斑块中的CD 4和IL-17 mRNA表达升高，外周中活化的CD 4（+）T细胞数量增加。缺乏Trim 21的初始T细胞向Th 17细胞的分化增加在体外得到证实，转录组学分析揭示了非致病性Th 17表型基因的上调。此外，基质金属蛋白酶（MMPs）的表达减少，在主动脉斑块。对人颈动脉斑块的分析证实，TRIM 21表达与关键Th 17基因和胶原蛋白的表达呈负相关，但与患者中的MMPs也呈正相关，将我们的研究结果与临床背景联系起来。斑块的表型。
Aims Patients with hyperlipidemia are at risk of atherosclerosis, but not all develop cardiovascular disease, highlighting the importance of other risk factors such as inflammation. Both the innate and adaptive arms of the immune system have been suggested in the initiation and propagation of plaque formation. Tri-partite motif (TRIM) 21 is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in chronic inflammatory disease. Here, we investigate a potential role for TRIM21 in coronary artery disease.Methods and results Trim21-deficient or wild-type bone marrow was transplanted into Ldlr(-/-) mice fed a hypercholesterolemic diet. The Trim21(-/-)->Ldlr(-/-) mice developed larger atherosclerotic plaques, with significantly higher collagen content compared to mice transplanted with wild-type cells. High collagen content of the atheroma is stabilizing, and has recently been linked to IL-17. Interestingly, Trim21(-/-)-> Ldlr(-/-) mice had elevated CD4 and IL-17 mRNA expression in plaques, and increased numbers of activated CD4(+) T cells in the periphery. An increased differentiation of naive T cells lacking Trim21 into Th17 cells was confirmed in vitro, with transcriptomic analysis revealing upregulation of genes of a nonpathogenic Th17 phenotype. Also, decreased expression of matrix metalloproteinases (MMPs) was noted in aortic plaques. Analysis of human carotid plaques confirmed that TRIM21 expression negatively correlates with the expression of key Th17 genes and collagen, but positively to MMPs also in patients, linking our findings to a clinical setting.Conclusion In this study, we demonstrate that TRIM21 influences atherosclerosis via regulation of Th17 responses, with TRIM21 deficiency promoting IL-17 expression and a more fibrous, stable, phenotype of the plaques.