The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

Abstract

SummaryFrom studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen‐associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL‐1 and IL‐18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin‐associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, ex vivo studies of human cells and murine cells, and in vivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

The Role of Inflammasome in Abdominal Aortic Aneurysm and Its Potential Drugs

“…When th central protein NLRP3 is stimulated by activation signals, ASC interacts with the PYD o NLRP3 via homotypic PYD, followed by recruiting pro-caspase-1 with CARD-CARD in teractions, resulting in inflammasome oligomerization (Figure 1) [35]. Then, pro-caspase 1 cleaves itself into active caspase-1, which subsequently mediates pro-IL-1β, pro-IL-18 and GSDMD to cleave into active subunits, triggering pyroptosis and inflammation [36] Due to its ability to be activated by manifold types of pathogens or danger signals, NLRP inflammasome can play a pivotal role in various disease processes, namely, cryopyrin associated periodic syndromes (CAPS) [37,38], Alzheimer's disease [39], rheumatoid ar thritis [40], and others [41]. Additionally, many studies have suggested a correlation be tween NLRP3 inflammasome and AAA in recent years.…”