Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Macrophage-derived IL-1α but not IL-1β exacerbates atherosclerosis.
Figure 2: Fatty acids that accumulate in atherosclerotic plaques selectively stimulate macrophage foam cells to produce IL-1α.
Figure 3: OA elicits inflammasome-independent, IL-1α-mediated inflammation in vitro and in vivo.
Figure 4: Functional impairment of IL-1α secretion in IL-1β-deficient macrophages.
Figure 5: Dietary OA induces foam-cell formation, vascular inflammation and atherogenesis in vivo.
Figure 6: Fatty acid–induced mitochondrial uncoupling is independent of PPAR and FFAR1 receptors for fatty acids.
Figure 7: Fatty acid–induced mitochondrial uncoupling and calcium-signaling deviates IL-1β responses toward IL-1α secretion.
Figure 8: OA-induced mitochondrial uncoupling, calcium fluxes and IL-1α production are regulated in part by mitochondrial UCP2.

Similar content being viewed by others

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.

References

  1. Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hansson, G.K., Robertson, A.-K.L. & Söderberg-Nauclér, C. Inflammation and atherosclerosis. Annu. Rev. Pathol. 1, 297–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Berliner, J.A. & Watson, A.D. A role for oxidized phospholipids in atherosclerosis. N. Engl. J. Med. 353, 9–11 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Shibata, N. & Glass, C.K. Macrophages, oxysterols and atherosclerosis. Circ. J. 74, 2045–2051 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Fazio, S. et al. Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc. Natl. Acad. Sci. USA 94, 4647–4652 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Llodrá, J. et al. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc. Natl. Acad. Sci. USA 101, 11779–11784 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chamberlain, J. et al. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS ONE 4, e5073 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Devlin, C.M., Kuriakose, G., Hirsch, E. & Tabas, I. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc. Natl. Acad. Sci. USA 99, 6280–6285 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Merhi-Soussi, F. et al. Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice. Cardiovasc. Res. 66, 583–593 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Isoda, K. et al. Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 24, 1068–1073 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Matsuki, T. et al. Involvement of tumor necrosis factor-α in the development of T cell-dependent aortitis in interleukin-1 receptor antagonist-deficient mice. Circulation 112, 1323–1331 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Nicklin, M.J., Hughes, D.E., Barton, J.L., Ure, J.M. & Duff, G.W. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J. Exp. Med. 191, 303–312 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kamari, Y. et al. Differential role and tissue specificity of interleukin-1α gene expression in atherogenesis and lipid metabolism. Atherosclerosis 195, 31–38 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Kirii, H. et al. Lack of interleukin-1β decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 656–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Franchi, L., Eigenbrod, T., Muñoz-Planillo, R. & Nuñez, G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241–247 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Dinarello, C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Freigang, S. et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41, 2040–2051 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Rajamäki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE 5, e11765 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Menu, P. et al. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis. 2, e137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ridker, P.M., Thuren, T., Zalewski, A. & Libby, P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 162, 597–605 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Kansanen, E. et al. Nrf2-dependent and -independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as the major pathway activated by nitro-oleic acid. J. Biol. Chem. 284, 33233–33241 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fettelschoss, A. et al. Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression. Proc. Natl. Acad. Sci. USA 108, 18055–18060 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shornick, L.P. et al. Mice deficient in IL-1β manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183, 1427–1436 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Kamari, Y. et al. Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α. Biochem. Biophys. Res. Commun. 405, 197–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Van De Parre, T.J.L. et al. Mitochondrial uncoupling protein 2 mediates temperature heterogeneity in atherosclerotic plaques. Cardiovasc. Res. 77, 425–431 (2007).

    Article  PubMed  CAS  Google Scholar 

  30. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Kanneganti, T.-D. & Dixit, V.D. Immunological complications of obesity. Nat. Immunol. 13, 707–712 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Osborn, O. & Olefsky, J.M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Masters, S.L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gurcel, L., Abrami, L., Girardin, S., Tschopp, J. & van der Goot, F.G. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135–1145 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Im, S.-S. et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 13, 540–549 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Elhage, R. et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res. 59, 234–240 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Keller, M., Rüegg, A., Werner, S. & Beer, H.-D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Groß, O. et al. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36, 388–400 (2012).

    Article  PubMed  CAS  Google Scholar 

  44. Chen, C.-J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat. Med. 13, 851–856 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Di Paolo, N.C. et al. Virus binding to a plasma membrane receptor triggers interleukin-1α-mediated proinflammatory macrophage response in vivo. Immunity 31, 110–121 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Zhou, R., Yazdi, A.S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Folch, J., Lees, M. & Sloane Stanley, G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    Article  CAS  PubMed  Google Scholar 

  50. Lepage, G. & Roy, C.C. Direct transesterification of all classes of lipids in a one-step reaction. J. Lipid Res. 27, 114–120 (1986).

    Article  CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Stefan Freigang or Manfred Kopf.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 142 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2704

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing