Cholesterol efflux, CHIP and inflammasome activation

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Project Summary/Abstract Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in the US. Despite the benefits of LDL lowering therapies, there remains a large burden of residual CVD, related to persistent dyslpidemia and inflammation. Even though CANTOS and colchicine trials have established the benefit of anti-inflammatory therapies, these approaches were associated with a significant increase in infectious complications, limiting their clinical application. This suggests the need for a deeper understanding of the links between dyslipidemia and atherosclerotic inflammation, leading to more effective targeting of relevant mechanisms and susceptible populations. This grant has supported studies of the mechanisms linking defective cholesterol efflux pathways to macrophage and neutrophil inflammatory processes, including NLRP3 inflammasome activation and neutrophil extracellular trap (NET) formation. We recently discovered a new pathway linking macrophage cholesterol accumulation (mediated through defective cholesterol efflux or loading with modified LDL) to ER cholesterol accumulation and activation of a signaling pathway that leads to deubiquitylation and assembly of the NLRP3 inflammasome. Inhibition of this pathway with the deubiquitinase inhibitor holomycin led to reduced atherosclerosis and NETosis, suggesting a new approach to reducing inflammasome activation and atherosclerosis. The same pathway appears to be activated in TET2 clonal hematopoiesis. The proposed studies will further explore the role of the newly defined pathway in promoting NLRP3 inflammasome activation and atherosclerosis in hyperlipidemic mice with defective cholesterol efflux or TET2 clonal hematopoiesis and in human cells containing TET2 mutations. The ability of reconstituted HDL to promote cholesterol efflux and to reverse inflammasome activation, leading to plaque stabilization, will also be investigated. The proposal should provide new mechanistic insights into the links between macrophage cholesterol accumulation and plaque inflammation and will evaluate novel precision therapeutic approaches to atherosclerosis.