Targeting the NLRP3 Inflammasome to Reduce Vascular Endothelium Dysfunction
Chronic inflammation is a potent mechanism in aging, disruptive of tissue function throughout the body. The focus in today's open access paper is on the effects of inflammatory signaling in blood vessel walls, particularly on the endothelial cells that play a role in maintaining the ability of blood vessels to contract and dilate. Dysfunction in blood vessels throughout the body causes harms ranging from hypertension to blood-brain barrier leakage to reduced blood flow that impacts the function of muscle and brain tissue.
Approaches to suppressing inflammatory signaling developed and brought to the clinic have to date taken the form of blunt blockades of important signaling molecules, such as TGF-α, or core processes in immune cell function, such as antigen presentation. Unfortunately, this causes as many problems over the long-term as it brings benefits in cases of inflammatory disease. Short-term inflammation is critical to the function of the immune system in its roles in defending against pathogens, tissue maintenance, and regeneration from injury. But therapies do not well distinguish between good inflammation and bad inflammation, suppressing both.
There is the hope that approaches targeting the NLRP3 inflammasome and related biochemistry will prove to be at least incrementally more selective, as discussed here, but it is likely that realization of the goal of effective, minimally harmful inhibitors of chronic inflammation lies still further in the future.
Vascular aging is a multifaceted and complex process that ultimately renders the vessels prone to profound functional and structural disturbances that favor cardiovascular disease. One of the main mechanisms contributing to vascular aging is endothelial cell senescence. Senescent cells undergo functional and morphological changes that ultimately lead to growth arrest while remaining metabolically active. Importantly, these cells acquire a senescence-associated secretory phenotype (SASP), which results in the over-production and release of a wide array of cytokines and chemokines. The SASP favors leukocyte recruitment and is considered a main driver of sterile age-related inflammation or "inflammaging". Functionally, endothelial cell senescence is tightly associated with endothelial dysfunction and defective vasodilatation, considered as early markers of vascular disease and atherosclerosis.
In the present study, we have evaluated whether a positive feedback of IL-1β in the NLRP3 inflammasome via NF-κB could promote human endothelial senescence in vitro and murine endothelial dysfunction in vivo. Our results indicate that the NLRP3 inflammasome is pivotal in mediating the detrimental effects of IL-1β, showing that auto-activation is a crucial feature boosting endothelial cell senescence in vitro, which is paralleled by vascular dysfunction in vivo. Hence, the inhibitor of NLRP3 inflammasome assembly, MCC 950, was able to disrupt the aforementioned positive loop, thus alleviating inflammation, cell senescence and vascular dysfunction.
Besides, we explored alternative NLRP3 inflammasome inhibitory agents such as the RAS heptapeptide Ang-(1-7) and the anti-aging protein klotho, both of which demonstrated protective effects in vitro and in vivo. Altogether, our results highlight a fundamental role for the hereby described NLRP3 inflammasome/IL-1β positive feedback loop in stress-induced inflammaging and the associated vascular dysfunction, additionally providing evidence of a potential therapeutic use of MCC 950, Ang-(1-7) and recombinant klotho to block this loop and its deleterious effects.