NLRP3 Inflammasome Activation in Endothelial Dysfunction and Atherosclerosis

The NLRP3 inflammasome is a molecular platform within vascular cells that senses a variety of danger signals—ranging from cholesterol crystals and oxidised lipoproteins to metabolic stressors such as hyperglycaemia and homocysteine. Upon activation, NLRP3 recruits and activates caspase-1, driving the maturation and release of pro-inflammatory cytokines interleukin-1β and interleukin-18 and promoting a specialised form of inflammatory cell death known as pyroptosis. In the endothelium, this cascade compromises barrier integrity, enhances leukocyte adhesion and transmigration, and fosters a local milieu of oxidative stress. Endothelial dysfunction is widely acknowledged as an early and critical event in the initiation of atherosclerotic plaque formation. There, the interplay between injured endothelial cells, activated macrophages and migrating smooth muscle cells accelerates lipid deposition, neointimal hyperplasia and plaque instability. Emerging evidence also implicates non-coding RNAs and epigenetic regulators, such as histone deacetylases, in fine-tuning NLRP3 activity. Conversely, several endogenous and exogenous modulators—among them the longevity factor SIRT1 and selective small-molecule inhibitors—have shown promise in restraining inflammasome activation without broadly suppressing innate immunity. This balance between preserving host defence and mitigating chronic sterile inflammation represents a pivotal frontier in cardiovascular therapeutics, with implications for device coatings, targeted drug delivery and lifestyle interventions aimed at reducing residual inflammatory risk.

Research from Nature Portfolio

No recent Nature Portfolio content available.

NLRP3 Inflammasome Activation in Endothelial Dysfunction and Atherosclerosis publication trend

The graph below shows the total number of articles in nlrp3 inflammasome activation in endothelial dysfunction and atherosclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

NLRP3 inflammasome: A multiprotein complex that detects cellular stress signals, activates caspase-1 and drives the release of IL-1β and IL-18.

Pyroptosis: A pro-inflammatory form of programmed cell death characterised by gasdermin pore formation, cell swelling and rapid lysis.

Endothelial dysfunction: Impairment of the vascular endothelium’s barrier, antithrombotic and anti-inflammatory functions, marking an early stage of atherogenesis.

Neointimal hyperplasia: Proliferation and migration of smooth muscle cells into the intima, leading to thickened vessel walls and luminal narrowing.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that serve as signalling intermediates but can also trigger oxidative damage when in excess.

References

1. Selective NLRP3 Inflammasome Inhibitor MCC950 Suppresses Inflammation and Facilitates Healing in Vascular Materials. Advanced Science (2023).
2. Roles of pyroptosis in atherosclerosis pathogenesis. Biomedicine & Pharmacotherapy (2023).
3. Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder. Molecular Medicine (2023).
4. HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell Death Discovery (2022).
5. Fucoidan modulates SIRT1 and NLRP3 to alleviate hypertensive retinopathy: in vivo and in vitro insights. Journal of Translational Medicine (2024).
6. NLRP3 inflammasome in endothelial dysfunction. Cell Death & Disease (2020).