Cholesterol, Inflammasomes, and Atherogenesis

Plasma cholesterol levels have been strongly associated with atherogenesis, underscoring the role of lipid metabolism in defining cardiovascular disease risk. However, the atherosclerotic plaque is highly dynamic and contains elements of both the innate and adaptive immune system that respond to the aberrant accumulation of lipids in the subendothelial space. Previous research has focused on defining how proinflammatory cytokines synthesized by macrophages, such as interleukin-1β (IL-1β), modulate the progression of atherosclerosis, supporting the notion that chronic inflammation accelerates atherogenesis. More recently, emphasis has been placed on the elucidation of the mechanisms that contribute to pro–IL-1β production and finally its processing via multiprotein complexes termed the inflammasomes, a family of cytosolic multiprotein complexes that serve as sensors of either pathogen invasion or cellular stress (ie, cholesterol crystals) and work via triggering caspase-1–mediated processing of pro–IL-1β to IL-1β. Based on this link between cholesterol metabolism, NLRP3 inflammasome activation, and IL-1β release, it is important to re-evaluate how the atherogenic environment stimulates immune cells to produce IL-1β.