STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases
STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases
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DOI：
10.1093/eurheartj/ehab249
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发表时间：
2021-07-06
影响因子：
39.3
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Pham, Phuong Tran;Fukuda, Daiju;Sata, Masataka
生活方式相关疾病促进动脉粥样硬化，一种慢性炎症性疾病;然而，分子机制仍然在很大程度上未知。在过度营养条件下释放的内源性DNA片段通过DNA传感器的识别引起无菌性炎症。在这里，我们研究了干扰素基因刺激因子（STING），一种胞质DNA传感器，在动脉粥样硬化形成中的作用。喂食西式饮食（WTD）的Apoe（-/-）小鼠（一种高胆固醇血症小鼠模型）显示出更高的STING表达和DNA损伤标记物，如γ H2 AX，p53，和单链DNA（ssDNA）积累在巨噬细胞在主动脉与野生型（WT）小鼠相比。Apoe（-/-）小鼠主动脉中的cGAMP（STING激动剂）水平更高。与对照组相比，Apoe（-/-）小鼠中Sting基因的缺失减少了主动脉弓中的动脉粥样硬化病变、斑块中的脂质和巨噬细胞积聚以及主动脉中的炎症分子表达。使用特异性抑制剂C-176对STING进行药理学阻断可改善Apoe（-/-）小鼠的动脉粥样硬化形成。相反，Apoe（-/-）小鼠骨髓特异性STING表达刺激动脉粥样硬化形成。STING的表达或缺失不影响代谢参数和血压。体外研究显示，通过cGAMP或线粒体DNA的STING活化加速小鼠和人巨噬细胞中的炎性分子表达（例如TNF-α或IFN-β）。核因子-κ B和TANK结合激酶1的激活参与了STING相关的血管炎症和巨噬细胞激活。结论干扰素基因刺激因子可刺激巨噬细胞的促炎性活化，导致动脉粥样硬化的发生发展。干扰素基因信号刺激因子可能成为动脉粥样硬化潜在的治疗靶点。STING信号最初与先天免疫系统相关，通过将生活方式相关疾病与慢性炎症性疾病联系起来，可能提供一种新的动脉粥样硬化发生机制，并作为动脉粥样硬化的潜在治疗靶点。
Aims Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.Methods and results Apolipoprotein E-deficient (Apoe(-/-)) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as gamma H2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe(-/-) mice. Genetic deletion of Sting in Apoe(-/-) mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe(-/-) mice. In contrast, bone marrow-specific STING expression in Apoe(-/-) mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-alpha or IFN-beta) in mouse and human macrophages. Activation of nuclear factor-kappa B and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP.Conclusion Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.[GRAPHICS]STING signalling, originally associated with innate immune system, may provide a novel mechanism of atherogenesis by linking lifestyle-related diseases to chronic inflammatory disease and serve as a potential therapeutic target for atherosclerosis.