P1942A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signaling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity

Abstract

Abstract A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signalling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity Objectives We aimed to investigate interleukin (IL)-1 generation and the regulatory role of inflammasome in human advanced atherosclerosis. Background IL-1β is key contributor to the inflammatory process associated with atherosclerosis and its complications. Recent studies suggested that IL-1β blockade reduces the burden of inflammation and recurrence of cardiovascular events. Yet, other cytokines in IL-1 family and the regulation of IL-1 generation in patients with atherosclerosis remains poorly understood. Methods and results A focused transcriptomic analysis in human atherosclerotic specimens discovered that human atherosclerotic plaques host a broad reservoir of inflammasome components, characterised by expression of canonical inflammasome gene NLRP6, NLRP12, NLRC4, NLRP3 and non-canonical inflammasome gene caspase 4 significantly elevated in the symptomatic plaques versus the asymptomatic plaques. Upregulation of NLRP3 inflammasome expression in plaque validated by immunohistochemistry staining suggested it as a distinctive characteristic of plaque vulnerability and complexity. Functional studies on atherosclerotic explants obtained from patients undergoing carotid endarterectomy revealed constitutive generation of IL-1β accompanied by secretion of comparable levels of IL-1α from the majority of the plaques, while IL-18 and IL-33 generation from some of the plaques. Stimulation of the plaques with inflammasome activators showed an inducible generation of both IL-1α and IL-1β, not IL-18 or IL-33, mediated by specific canonical and non-canonical inflammasome pathways. Analysis on the medication records of these patients indicated that plaques from patients with suboptimally controlled hyperlipidemia, imaging signs for plaque instability and inadequate statins therapy possessed higher recruitable production of IL-1β, suggesting the conventional atherogenic factor in regulation of inflammasome immunity and disease activity. Mechanistic studies on tissue and cells isolated from atheromatous plaques demonstrate that generation of mature IL-1β is via a mechanism controlled by NLRP3 and the effector caspase-1. Conclusions The study supports a profound canonical and non-canonical inflammasomes mediated plaque IL-1α/β generation, via a key mechanism by NLRP3 and caspase-1. The results provide biological insights into the clinical merit of high-intensity cholesterol lowering and anti-IL-1 signalling-directed therapies in high-risk patients with atherosclerosis. Acknowledgement/Funding KI-Mayo collaboration project, the Swedish Research Council, the Swedish Heart-Lung Foundation, European Union FP7 projects, the NIH