Uncovering the role of extracellular ASC danger particles in atherosclerosis and gout

Atherosclerosis is a chronic inflammatory disorder, a leading cause of cardiovascular disease and a major life-threatening condition. It is well established that endogenous danger particles like cholesterol crystals, MSU crystals and amyloid beta are sensed by the NLRP3 inflammasome, which represents a major cytosolic pro-inflammatory pathway. One of the main components of the NLRP3 inflammasome complex is the adaptor protein ASC, which is required to link to pro-caspase-1 activation, cytokine release and pyroptotic cell death. Recent studies described a new mechanism to propagate inflammation, whereby release of extracellular ASC danger particles by pyroptosis act as danger signal to activate the NLRP3 inflammasome in bystander cells and also directly activate extracellular caspase-1. Interestingly, inflammatory responses in atherosclerosis and gout are mediated by cholesterol crystals and MSU crystals, which act as NLRP3-activating danger signals. Gout has increasingly been associated with a number of comorbidities, including cardiovascular disease, diabetes, obesity and chronic kidney disease, however the underlying mechanism remains largely unexplained. My hypothesis is that ASC particles are a novel risk factor for atherosclerosis and gout, which trigger and exacerbate these pathologies possibly by a harmful positive feedback loop. My goal is to investigate circulating ASC particles as a pathology factor associated with atherosclerosis in gout patients. To further dissect a link between atherosclerosis and gout, I will investigate a modulatory mechanism mediated by POP1, a protein that binds to ASC and represents a novel anti-inflammatory protein targeting inflammasome complexes in macrophages. This proposal aims to understand a unique molecular mechanism that enhances self-perpetuating inflammatory processes triggered by extracellular ASC particles in atherosclerosis and gout. I expect that results from this study are also broadly applicable to other inflammas