Inflammasomes and Atherosclerosis: a Mixed Picture

Abstract

The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.

Innate Immune Pathways in Atherosclerosis—From Signaling to Long-Term Epigenetic Reprogramming

“…Recently, Christ et al showed that Ldlr −/− /Nlrp3 −/− double knockout mice had significantly reduced atherosclerotic plaque sizes after 8 weeks of western-type diet feeding compared to Ldlr −/− mice [123]. However, contrasting findings have been reported for the role of NLRP3 in atherosclerosis, and it is important to acknowledge the remarkable influence of factors such as gender, age, specific diet, duration of atherogenic diet feeding, and environmental conditions on the phenotype of NLRP3-deficient mice [14,15]. These should be accounted for when designing therapeutic strategies to inhibit NLRP3 for atheroprotection.…”

“…NLRP3 is activated by various DAMPs, such as cholesterol crystals, oxLDL, and HSPs. Upon activation, NLRP3 triggers the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18, which further contribute to atherogenesis by inducing the expression of adhesion molecules and chemokines in endothelial cells and enhancing the recruitment and activation of immune cells such as macrophages [13][14][15].…”

Atherosclerosis and Bidirectional Relationship between Cancer and Cardiovascular Disease: From Bench to Bedside—Part 1

“…The growth of an atherosclerotic plaque is a chronic dynamic inflammatory process with many different players. Early in the atherogenesis, high levels of oxidized low-density lipoproteins (ox-LDL) and remnants of triglyceride-rich lipoproteins gain access to the subendothelial space eliciting a danger signal that activate the NOD [nucleotide oligomerization domain]-,LRR[leucine-rich repeat]-,and PYD [pyrin domain]-containing protein3 (NLRP3) inflammasome [49,50] in innate immune cells. The activated inflammasome starts a cascade of inflammatory cytokines (IL-1β, IL-6) and upregulates highsensitivity C-reactive protein (hs-CRP) in the liver that eventually leads to atherosclerotic lesions.…”

Editorial: Efficacy and mechanism of herbal medicines and their functional compounds in preventing and treating cardiovascular diseases and cardiovascular disease risk factors

“…AS is a chronic inflammatory disease of the vasculature, characterized by the formation of fibrous and fatty lesions on arterial walls, with a complex pathogenesis ( Tall and Bornfeldt, 2023 ).…”