NLRP3 Inflammasome in Vascular Disease: A Recurrent Villain to Combat Pharmacologically

Abstract

Despite the great advances in medicine, mortality from cardiovascular diseases keeps on growing. This tendency is not likely to change considering the pandemic proportions of obesity and diabetes. Besides, the global population is more aged as life expectancy increases, and vascular aging plays a key role in the increased risk of vascular disease. In light of recent trials, namely the CANTOS study, showing the enormous potential of anti-inflammatory therapies and in particular those targeted to IL-1β, a change in therapeutical management of cardiovascular diseases is coming about. The NLRP3 inflammasome is a multiprotein complex that assembles to engage the innate immune defense by processing the maturation of pro-inflammatory cytokines IL-1β and IL-18. Substantial evidence has positioned the NLRP3 inflammasome at the center of vascular disease progression, with a particular significance in the context of aging and the low-grade chronic inflammation associated (inflammaging). Therefore, pharmacological blockade of the NLRP3 inflammasome and its end products has arisen as an extremely promising tool to battle vascular disease. In this review, we discuss the mechanisms by which the NLRP3 inflammasome contributes to vascular disease, with particular attention to the consequences of aging, and we enumerate the therapeutic options available to combat this recurrent villain.

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

“…To date, several NLRP3 inflammasome activation pathways have been established: the canonical pathway which comprises of a two-signal model involving priming (signal 1) and activation (signal 2); a non-canonical pathway that necessitates caspase-4/caspase-5, secretion of IL-1β and IL-18 which respond to a particular intracellular lipopolysaccharide (LPS)-induced infection of gram-negative bacteria; and the alternative pathway driven by toll-like receptor 2 (TLR2) or TLR4 signaling without implicating additional secondary activators [35][36][37]. We further described the canonical pathway in the paragraphs that follow, given that is the main culprit for underlying atherosclerosis.…”

“…Since oxidized low-density-lipoproteins (oxLDLs) can generate the initiation signal, this may be sufficient to send the NLRP3 inflammasome to both the activation and the priming signals [53]. The uptake of oxLDL by macrophage scavenger receptors, such as cluster of differentiation (CD) 36, initiates the formation of a TLR4/TLR6 heterodimer, which further activates the inflammasome and triggers NF-κB signaling [36,54].…”

“…In addition, through sirtuin 1 and superoxide dismutase (SOD), tissular overexpression of MCC950 exhibited antioxidant capacity [132]. Regardless of the favorable outcomes in animal models, the compound is currently withheld from clinical trials because of its liver toxicity [24,36].…”

“…OLT1177, also referred to as dapanustrile, is a nitrile sulfonyl derivative that selectively inhibits the inflammasome ATPase activity, disabling NLRP3-ASC and NLRP3-caspase-1 interactions and IL-1β generation in neutrophils and monocyte-derived macrophages [136]. In a phase I clinical trial, dapanustrile, proved to be safe and tolerated in oral application in healthy adults, with both in vitro and in vivo efficacy distinguishing it from MCC950 [36,137].…”

Forsythoside B alleviates cerebral ischemia-reperfusion injury via inhibiting NLRP3 inflammasome mediated by SIRT1 activation

“…It can detect cellular deviation from homeostasis as a danger signal and then trigger inflammatory responses. This complex is linked to a broad spectrum of diseases, including auto-inflammatory, infectious, and autoimmune diseases [ 7 ]. NLRP3 interacts with ASC and subsequently cleaves pro-Caspase-1.…”