Unit of Experimental Rheumatology, Department of Medicine, Karolinska Insititutet, Center for Molecular Medicine L8:04, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Cardiovasc Res. 2018 Jan 1;114(1):158-167. doi: 10.1093/cvr/cvx181.
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.
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 naïve T cells lacking Trim21 into Th17 cells was confirmed in vitro, with transcriptomic analysis revealing upregulation of genes of a non-pathogenic 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.
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.
患有高血脂的患者有发生动脉粥样硬化的风险，但并非所有患者都会发展为心血管疾病，这凸显了炎症等其他危险因素的重要性。先天免疫和适应性免疫系统均被认为参与了斑块形成的启动和发展。三结构域蛋白 21（TRIM21）是组织炎症和促炎细胞因子产生的调节剂，并且与慢性炎症性疾病有关。在此，我们研究了 TRIM21 在冠状动脉疾病中的潜在作用。
将 Trim21 缺陷型或野生型骨髓移植到喂食高胆固醇饮食的 Ldlr-/- 小鼠中。与接受野生型细胞移植的小鼠相比，Trim21-/-/-->Ldlr-/- 小鼠形成的动脉粥样硬化斑块更大，胶原含量明显更高。动脉粥样硬化斑块中的高胶原含量具有稳定作用，最近与白细胞介素 17（IL-17）有关。有趣的是，Trim21-/-/-->Ldlr-/- 小鼠的斑块中 CD4 和 IL-17 mRNA 表达增加，外周血中活化的 CD4+T 细胞数量增加。体外实验证实，缺乏 Trim21 的幼稚 T 细胞向 Th17 细胞的分化增加，转录组分析显示非致病性 Th17 表型的基因上调。此外，还注意到主动脉斑块中基质金属蛋白酶（MMPs）的表达减少。对人颈动脉斑块的分析证实，TRIM21 的表达与关键 Th17 基因和胶原的表达呈负相关，但与 MMPs 的表达呈正相关，这将我们的发现与临床环境联系起来。
在这项研究中，我们证明了 TRIM21 通过调节 Th17 反应影响动脉粥样硬化，TRIM21 缺乏促进了 IL-17 的表达，并使斑块呈现出更纤维化、更稳定的表型。
