Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis

Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1 beta production. We found here that atherogenesis was mediated by IL-1 alpha and we identified fatty acids as potent inducers of IL-1 alpha-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1 alpha but not of IL-1 beta by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1 beta secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1 alpha. Our findings delineate a previously unknown pathway for vascular immunopathology that links the cellular response to metabolic stress with innate inflammation, and suggest that IL-1 alpha, not IL-1 beta, should be targeted in patients with cardiovascular disease.