Role of NLRP3 Inflammasomes in Atherosclerosis

Abstract

Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…For instance, relevant preclinical models indicate a potent anti‐inflammatory effect of BHB, and observational studies in patients subjected to ketogenic diets (KDs) are consistent with this observation . Accordingly, low‐grade inflammation (LGI) is a recognized factor that contributes to the development and progression of atherosclerosis and is more generally a relevant risk factor for CV disease and mortality . LGI is defined as a chronic, sterile, cold, systemic and multifactorial pro‐inflammatory status .…”

“…The inflammasome platforms are constituted by a NOD‐like receptor (NLR)‐caspase 1‐IL‐1β cascade that can be activated by a plethora of metabolic and/or injury‐derived by‐products, resulting in chronic secretion of pro‐inflammatory cytokines. Inflammasome activation is a promising target to ameliorate LGI in T2DM and halt the progression of the atherosclerotic process . Notably, BHB inhibits the NLRP3 inflammasome by preventing K + efflux without undergoing oxidation in the Krebs cycle.…”

“…Overall, the cumulative anti‐inflammatory effect of SGLT2 inhibitors could be the result of four possible mechanisms: (1) increased plasma levels of anti‐inflammatory ketone bodies, such as BHB; (2) decreased interfacing of immune cells with glucose; (3) decreased secretion of insulin; and (4) decreased circulating levels of uric acid. These mechanisms are likely to be complementary, rather than mutually exclusive, all converging on one primary target, that is, IL‐1β, a major cytokine with a recognized role in the development of atherosclerosis and CV disease (Figure ). Finally, a glycaemia‐independent, molecule‐intrinsic, anti‐inflammatory mechanism has been proposed for canagliflozin and dapagliflozin, as has been shown in vitro in vascular endothelial cells and cardiofibroblast …”

“…Endothelial dysfunction, recruitment and infiltration of white blood cells in both innate and acquired immunity, lipid oxidation, deposition and accumulation, proliferation of smooth muscle cells, intima‐media thickening and plaque destabilization/rupture can all be promoted by soluble inflammatory mediators. Conventional risk factors such as dysglycaemia, dyslipidaemia and high blood pressure can all foster the inflammatory response in endothelial cells, macrophages and smooth muscle cells, and can challenge the vessel wall for an entire lifespan . Of note, while atherosclerosis is a slowly appearing process, the effect of inflammation on plaque stabilization can influence the incidence of CV events within a relatively short time period .…”

Anti-Inflammatory Therapy for Atherosclerosis: Contribution to and Lessons of Rheumatology

“…Дефицит ИЛ1β у лабораторных живот-ных отменяет формирование атеросклеротических бля-шек, в то время как введение экзогенного ИЛ1, приводит к утолщению комплекса интима-медиа (КИМ) сосуди-стой стенки. При рассмотрении молекулярных механиз-мов развития атеросклероза, связанных с ИЛ1β, привлека-ют внимание данные о способности кристаллов холестери-на (ХС) и других «проатерогенных» факторов индуциро-вать синтез ИЛ1β за счет активации сборки NLRP3-ин-фламмасомы [22] (рис. 1).…”