Targeting the NLRP3 inflammasome in cardiovascular diseases

Abstract

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, activation of the NLRP3 inflammasome results in cytokine production, primarily interleukin(IL)-1β and IL-18, and, eventually, inflammatory cell death – pyroptosis. While a balanced inflammatory response favors damage resolution 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 pharmacological 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 development, multiple randomized trials have demonstrated the safety and efficacy of IL-1 blockade in atherothrombosis, 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 review, 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.