Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets

Abstract

We are witnessing the globalization of a specific type of arteriosclerosis with rising prevalence, incidence and an overall cardiovascular disease burden. Currently, atherosclerosis increasingly affects the younger generation as compared to previous decades. While early preventive medicine has seen improvements, research advances in laboratory and clinical investigation promise to provide us with novel diagnosis tools. Given the physio-pathological complexity and epigenetic patterns of atherosclerosis and the discovery of new molecules involved, the therapeutic field of atherosclerosis has room for substantial growth. Thus, the scientific community is currently investigating the role of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a crucial component of the innate immune system in different inflammatory disorders. NLRP3 is activated by distinct factors and numerous cellular and molecular events which trigger NLRP3 inflammasome assembly with subsequent cleavage of pro-interleukin (IL)-1β and pro-IL-18 pathways via caspase-1 activation, eliciting endothelial dysfunction, promotion of oxidative stress and the inflammation process of atherosclerosis. In this review, we introduce the basic cellular and molecular mechanisms of NLRP3 inflammasome activation and its role in atherosclerosis. We also emphasize its promising therapeutic pharmaceutical potential.

Fatal attractions that trigger inflammation and drive atherosclerotic disease

“…Such an enhanced inflammatory response contributes to CVD development. Accordingly, clinical trials in which CVD patients are treated with various biologics that target the NLRP3 inflammasome pathway demonstrate a reduction in atherothrombosis 44,45 . In summary, these reports demonstrate the critical role that inflammation plays in CVD development and how targeting novel inflammatory activators are crucial in further modulating disease progression.…”

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

“…Hyperactivation of the NLRP3 inflammasome is linked to the pathogenic progression of ASCVD ( Abbate et al, 2020 ). Duewell et al ( Tanase et al, 2023 ) demonstrated the NLRP3 inflammasome’s critical role in AS by using LDL receptor (LDLR)-deficient mice with NLRP3 −/− , ASC −/− , and IL-1α/β−/− bone marrow. 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.…”

Inflammasomes in Atherosclerosis—From Pathophysiology to Treatment

“…Inflammasome activation consists of two stages: priming and activation [ 17 ]. The priming stage involves the transcriptional activation of inflammasome components and the proinflammatory cytokines pro-IL-1 and pro-IL-18, which is mediated by Toll-like receptors (TLRs) [ 17 ]. Priming causes inflammasome components to be synthesized and accumulated, preparing cells to react to later signals [ 17 ].…”

“…The inflammasome is activated when the sensor protein detects PAMPs or DAMPs [ 17 ]. Depending on the sensor protein and the type of input, the specific activation pathways might differ.…”