Inflammasomes: a preclinical assessment of targeting in atherosclerosis

INTRODUCTION: Inflammasomes are central to atherosclerotic vascular dysfunction with regulatory effects on inflammation, immune modulation, and lipid metabolism. The NLRP3 inflammasome is a critical catalyst for atherogenesis thus highlighting its importance in understanding the pathophysiology of atherosclerosis and for the identification of novel therapeutic targets and biomarkers for the treatment of cardiovascular disease. AREAS COVERED: This review includes an overview of macrophage lipid metabolism and the role of NLRP3 inflammasome activity in cardiovascular inflammation and atherosclerosis. We highlight key activators, signal transducers and major regulatory components that are being considered as putative therapeutic targets for inhibition of NLRP3-mediated cardiovascular inflammation and atherosclerosis. EXPERT OPINION: NLRP3 inflammasome activity lies at the nexus between inflammation and cholesterol metabolism; it offers unique opportunities for understanding atherosclerotic pathophysiology and identifying novel modes of treatment. As such, a host of NLRP3 signaling cascade components have been identified as putative targets for drug development. We catalog these current discoveries in therapeutic targeting of the NLRP3 inflammasome and, utilizing the CANTOS trial as the translational (bench-to-bedside) archetype, we examine the complexities, challenges, and ultimate goals facing the field of atherosclerosis research.