Cardiovascular Research Center, Centers for Inflammation, Translational and Clinical Lung Research and Thrombosis Research (C.D., F.S., Y. Shao, Y. Sun, K.X., Y.L., D.N., D.A., X.J., X.Y.), Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
Metabolic Disease Research (X.J., H.W., X.Y.), Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
Arterioscler Thromb Vasc Biol. 2021 Mar;41(3):1032-1046. doi: 10.1161/ATVBAHA.120.315452. Epub 2020 Dec 31.
Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.
先天免疫细胞在短暂暴露于内源性或外源性刺激后，会产生过度的免疫反应和长期的炎症表型，从而导致在返回非激活状态后对第二次挑战产生改变的反应。这种现象被称为训练免疫（TI）。TI 不仅对宿主防御和疫苗反应很重要，而且对心血管和代谢疾病等慢性炎症也很重要，如动脉粥样硬化。TI 可发生在先天免疫细胞中，如单核细胞/巨噬细胞、自然杀伤细胞、内皮细胞（EC）和非免疫细胞，如成纤维细胞。在这篇简短的综述中，我们分析了 TI 在 EC 中的意义，EC 除了巨噬细胞外，也被认为是先天免疫细胞。TI 可由多种刺激诱导，包括脂多糖、卡介苗（BCG）和氧化低密度脂蛋白（oxLDL），这些刺激被定义为心血管和代谢疾病的危险因素。此外，EC 中的 TI 对于炎症的有效性和向慢性炎症的转变是功能性的。在 TI 的诱导过程中，训练细胞的细胞代谢发生重排，包括增加糖酵解、谷氨酰胺分解、三羧酸循环代谢物的积累和乙酰辅酶 A 的产生增加，以及甲羟戊酸合成的增加。随后，这导致表观遗传重塑，导致染色质结构的重要变化，从而增加基因转录和增强促炎免疫反应。然而，TI 途径和炎症途径是分开的，以确保炎症缓解时记忆保持。此外，活性氧在 TI 中发挥依赖于上下文的作用。因此，TI 在 EC 和巨噬细胞病理学和慢性炎症中发挥重要作用。然而，进一步表征 EC 和巨噬细胞中的 TI 将为心血管疾病发病机制提供新的见解，并为新的治疗靶点提供新的见解。
