The emerging role of pyroptosis-related inflammasome pathway in atherosclerosis

Abstract

Atherosclerosis (AS), a chronic sterile inflammatory disorder, is one of the leading causes of mortality worldwide. The dysfunction and unnatural death of plaque cells, including vascular endothelial cells (VEC), macrophages, and vascular smooth muscle cells (VSMC), are crucial factors in the progression of AS. Pyroptosis was described as a form of cell death at least two decades ago. It is featured by plasma membrane swelling and rupture, cell lysis, and consequent robust release of cytosolic contents and pro-inflammatory mediators, including interleukin-1β (IL-1β), IL-18, and high mobility group box 1 (HMGB1). Pyroptosis of plaque cells is commonly observed in the initiation and development of AS, and the levels of pyroptosis-related proteins are positively correlated with plaque instability, indicating the crucial contribution of pyroptosis to atherogenesis. Furthermore, studies have also identified some candidate anti-atherogenic agents targeting plaque cell pyroptosis. Herein, we summarize the research progress in understating (1) the discovery and definition of pyroptosis; (2) the characterization and molecular mechanisms of pyroptosis; (3) the regulatory mechanisms of pyroptosis in VEC, macrophage, and VSMC, as well as their potential role in AS progression, aimed at providing therapeutic targets for the prevention and treatment of AS.

Glucagon-like peptide-1 receptor agonists: new strategies and therapeutic targets to treat atherosclerotic cardiovascular disease

“…After 8 weeks of high-fat diets, mice showed reduced levels of IL-18, caspase-1/11 in the bone marrow, and significantly reduced AS plaques ( Liaqat et al, 2020 ), providing the first solid evidence that NLRP3 inflammasome promotes AS development. Following this observation, Shi et al ( Xu et al, 2022 ) found upregulated levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in carotid atherosclerotic plaques from patients undergoing carotid endarterectomy, with unstable plaques expressing higher levels of these compounds as opposed to stable plaques. In contrast, inhibition of the NLRP3 signaling pathway by siRNA interference suppressed pro-inflammatory cytokines in high-fat diet-fed ApoE −/− mice ( Jin et al, 2022 ).…”

Role of pyroptosis in the pathogenesis and treatment of diseases

“… 134 , 135 , 136 Many risk factors are involved in the development of atherosclerosis, but the mechanisms are not completely understood. Recent studies have found that multiple risk factors trigger pyroptosis in atherosclerosis associated cells, including endothelial cells (ECs), macrophages, and smooth muscle cells (SMCs), 137 , 138 , 139 , 140 suggesting that pyroptosis plays an important role in the pathological development of atherosclerosis (Figure 3 ).…”

Macrophage death in atherosclerosis: potential role in calcification

“…Indeed, while apoptosis remains the predominant form of macrophage death in atherosclerosis, less-well characterized types of regulated necrosis, such as pyroptosis, necroptosis, parthanatos and ferroptosis have been reported ( 11 , 12 ) ( Figure 1 ). Pyroptosis occurring in response to bacterial infection, is accompanied by NLRP3 inflammasome activation and by maturation of pro-inflammatory cytokines IL-1β and IL-18 ( 13 , 14 ). Necroptosis is a form of cell death activated by death receptors, such as TNFR1, IFNR and TLR3/4 ( 15 ).…”