title: Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis.
abstract: 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-1β production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1β by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1β secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1α. 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-1α, not IL-1β, should be targeted in patients with cardiovascular disease.
authors.affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
authors.forename: Franziska
authors.initials: F
authors.lastname: Ampenberger
authors.forename: Adrienne
authors.initials: A
authors.lastname: Weiss
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D004041:Dietary Fats / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D000071246:Uncoupling Protein 2; D014657:Vasculitis / Q000378:metabolism* / Q000473:pathology
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071246:Uncoupling Protein 2; D019301:Oleic Acid