Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis

Previous work has shown that foamy macrophages accumulate desmosterol, a cholesterol biosynthetic intermediate. However, the participation of desmosterol in regulating the functions of cholesterol-laden macrophages in the physiological context of atherosclerosis has remained elusive. In this work, we selectively deplete desmosterol by overexpressing DHCR24, the enzyme that catalyzes the conversion of desmosterol into cholesterol, in myeloid cells and demonstrate that desmosterol content in atherosclerotic plaque macrophages controls their function and activation. Molecular analysis of macrophages isolated from lesions revealed that depletion of desmosterol increases the expression of interferon-regulated genes and genes associated with “classical” macrophage activation. Together, our work provides molecular insights into the intimate links between cholesterol metabolism and inflammatory responses of macrophages during atherogenesis.