Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Atherosclerosis. 2024 Sep;396:118541. doi: 10.1016/j.atherosclerosis.2024.118541. Epub 2024 Jul 14.
The cardiovascular complications of atherosclerosis are thought to arise from an inflammatory response to the accumulation of cholesterol-rich lipoproteins in the arterial wall. The positive outcome of CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) provided key evidence to support this concept and suggested that inflammasomes and IL-1β are important inflammatory mediators in human atherosclerotic cardiovascular diseases (ACVD). In specific settings NLRP3 or AIM2 inflammasomes can induce inflammatory responses in the arterial wall and promote the formation of unstable atherosclerotic plaques. Clonal hematopoiesis (CH) has recently emerged as a major independent risk factor for ACVD. CH mutations arise during ageing and commonly involves variants in genes mediating epigenetic modifications (TET2, DNMT3A, ASXL1) or cytokine signaling (JAK2). Accumulating evidence points to the role of inflammasomes in the progression of CH-induced ACVD events and has shed light on the regulatory pathways and possible therapeutic approaches that specifically target inflammasomes in atherosclerosis. Epigenetic dynamics play a vital role in regulating the generation and activation of inflammasome components by causing changes in DNA methylation patterns and chromatin assembly. This review examines the genetic and epigenetic regulation of inflammasomes, the intersection of macrophage cholesterol accumulation with inflammasome activation and their roles in atherosclerosis. Understanding the involvement of inflammasomes in atherosclerosis pathogenesis may lead to customized treatments that reduce the burden of ACVD.
动脉粥样硬化的心血管并发症被认为是由于富含胆固醇的脂蛋白在动脉壁中积累而引起的炎症反应。CANTOS（Canakinumab Anti-inflammatory Thrombosis Outcome Study）的积极结果为这一概念提供了关键证据，并表明炎症小体和 IL-1β 是人类动脉粥样硬化性心血管疾病（ACVD）中的重要炎症介质。在特定情况下，NLRP3 或 AIM2 炎症小体可在动脉壁中诱导炎症反应，并促进不稳定的动脉粥样硬化斑块的形成。克隆性造血（CH）最近已成为 ACVD 的主要独立危险因素。CH 突变在衰老过程中产生，通常涉及调节表观遗传修饰（TET2、DNMT3A、ASXL1）或细胞因子信号（JAK2）的基因中的变体。越来越多的证据表明炎症小体在 CH 诱导的 ACVD 事件的进展中起作用，并阐明了炎症小体在动脉粥样硬化中的调节途径和可能的治疗方法。表观遗传动态在调节炎症小体成分的产生和激活方面起着至关重要的作用，可引起 DNA 甲基化模式和染色质组装的变化。本综述探讨了炎症小体的遗传和表观遗传调控、巨噬细胞胆固醇积累与炎症小体激活的交集及其在动脉粥样硬化中的作用。了解炎症小体在动脉粥样硬化发病机制中的作用可能会导致针对 ACVD 的定制治疗，从而减轻其负担。
