Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York (A.R.T.).
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle (K.E.B.).
Circ Res. 2023 May 26;132(11):1505-1520. doi: 10.1161/CIRCRESAHA.123.321637. Epub 2023 May 25.
The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.
CANTOS（Canakinumab 抗炎血栓结局研究）和秋水仙碱试验表明炎症小体及其主要产物白细胞介素 1β（IL-1β）在人类动脉粥样硬化性心血管疾病中具有重要作用。此外，小鼠模型研究表明炎症小体和 IL-1β 在动脉粥样硬化中具有因果关系。然而，最近的研究使人们对炎症小体在动脉粥样硬化中的作用有了更细致的认识。在高脂血症小鼠模型中的研究表明，NLRP3 炎症小体的显著激活需要二次打击，如胆固醇外排缺陷、DNA 修复缺陷、克隆性造血或糖尿病。同样，在人类中，一些促进克隆性造血的突变通过促进炎症小体激活，部分增加了冠心病的风险。最近在小鼠和人类中的研究表明，AIM2（黑色素瘤 2 缺失）炎症小体在促进心血管疾病方面发挥着更广泛的作用，包括在某些形式的克隆性造血和糖尿病中。这些进展表明，采用一种精准医疗方法，针对炎症小体或 IL-1β 的治疗方法可能最适合于涉及炎症小体激活增加的临床环境。
