Targeting the NLRP3 inflammasome in cardiovascular diseases

The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is an intracellular sensing protein complex that plays a major role in innate immunity. Following tissue injury, ac-tivation of the NLRP3 inflammasome results in cytokine production, primarily interleukin(IL)-1 beta and IL-18, and, eventually, inflammatory cell death - pyroptosis. While a balanced inflammatory response favors damage reso-lution and tissue healing, excessive NLRP3 activation causes detrimental effects. A key involvement of the NLRP3 inflammasome has been reported across a wide range of cardiovascular diseases (CVDs). Several pharmacologi-cal agents selectively targeting the NLRP3 inflammasome system have been developed and tested in animals and early phase human studies with overall promising results. While the NLRP3 inhibitors are in clinical develop-ment, multiple randomized trials have demonstrated the safety and efficacy of IL-1 blockade in atherothrombo-sis, heart failure and recurrent pericarditis. Furthermore, the non-selective NLRP3 inhibitor colchicine has been recently shown to significantly reduce cardiovascular events in patients with chronic coronary disease. In this re-view, we will outline the mechanisms driving NLRP3 assembly and activation, and discuss the pathogenetic role of the NLRP3 inflammasome in CVDs, providing an overview of the current and future therapeutic approaches targeting the NLRP3 inflammasome. (c) 2021 Elsevier Inc. All rights reserved.