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.
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Change history
12 March 2014
In the version of this article initially published, the key labels in Figure 3d are incorrect. The correct key should identify open bars as 'WT' and filled bars as 'Il1r1-/-'. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank W.-D. Hardt (Swiss Federal Institute of Technology (ETH) Zurich) for Casp1−/− (Casp1tm1Sesh) mice; J. Tschopp (University of Lausanne) for Nlrp3−/− (Nlrp3tm1Tsc) mice; M. Labow (Novartis) for Il1r1−/− (Il1r1tm1Roml) mice; H. Edlund (Umea University) for Ffar1−/− (Ffar1tm1Heed) bone marrow; W. Wahli (University of Lausanne) for Ppara−/− (Pparatm1Gonz) mice; S. Ibrahim (University of Lübeck) for Ucp2−/− (Ucp2tm1Lowl) mice; and the personnel of the animal facilities for technical assistance. Supported by the Swiss National Science Foundation (310030-124922/1 to M.K.) and the Swiss Federal Institute of Technology Zurich (ETH-18 09-1 to M.K. and S.F.).
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S.F. conceived of the project and designed the experiments; S.F. and F.A. did most of the experiments; A.W. did specific experiments; S.F., F.A. and A.W. analyzed data; M.H., T.-D.K., Y.I. and M.K. provided reagents; M.K. obtained the funding; and S.F. wrote the manuscript.
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Freigang, S., Ampenberger, F., Weiss, A. et al. Fatty acid–induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat Immunol 14, 1045–1053 (2013). https://doi.org/10.1038/ni.2704
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DOI: https://doi.org/10.1038/ni.2704
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