Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis
Xinbo Zhang, Jeffrey G. McDonald, Binod Aryal, Alberto Canfrán‐Duque, Emily L. Goldberg, Elisa Araldi, Wen Ding, Yuhua Fan, Bonne M. Thompson, Abhishek K. Singh, Qian Li, George Tellides, José Ordovás-Montañés, Rolando García-Milian, Vishwa Deep Dixit, Elina Ikonen, Yajaira Suárez, Carlos Fernández‐Hernando
Abstract
cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.