• A Corrigendum to this article was published on 29 July 2010

Abstract

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation1. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome2,3, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1α/β-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (to E.L. and K.L.R.) and from the Deutsche Forschungsgemeinschaft (GK 1202, to M.S. and P.D.).

Author information

Author notes

    • Peter Duewell
    • , Hajime Kono
    • , Veit Hornung
    •  & Eicke Latz

    These authors contributed equally to this work.

Affiliations

  1. Department of Infectious Diseases and Immunology and,

    • Peter Duewell
    • , Cherilyn M. Sirois
    • , Gregory Vladimer
    • , Egil Lien
    • , Katherine A. Fitzgerald
    •  & Eicke Latz
  2. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Hajime Kono
    •  & Kenneth L. Rock
  3. Department of Medicine, Division of Gastroenterology, University of Munich, 80336 Munich, Germany

    • Peter Duewell
    •  & Max Schnurr
  4. Leon H. Charney Division of Cardiology, New York University, New York, New York 10016, USA

    • Katey J. Rayner
    •  & Kathryn J. Moore
  5. Harvard Medical School, Lipid Metabolism Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Katey J. Rayner
    • , Kathryn J. Moore
    •  & Veit Hornung
  6. Institute of Clinical Chemistry and Pharmacology and,

    • Franz G. Bauernfeind
  7. Institute of Innate Immunology, University Hospitals, University of Bonn, 53127 Bonn, Germany

    • Eicke Latz
  8. Department of Medicine, Division of Cardiology, Michigan State University, East Lansing, Michigan 48824, USA

    • George S. Abela
  9. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Luigi Franchi
    •  & Gabriel Nuñez
  10. Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, 7491, Norway

    • Terje Espevik
    •  & Eicke Latz
  11. Cardiovascular Therapeutics, CSL Limited, Parkville, Victoria 3052, Australia

    • Samuel D. Wright

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Contributions

P.D., H.K., K.J.R, C.M.S., G.V., F.G.B, V.H., L.F. and E. Latz designed and performed experiments and analysed data. G.S.A. collected and prepared human samples. T.E., G.N., M.S., K.J.M., G.S.A., K.A.F. and E. Lien provided critical suggestions and discussions throughout the study. P.D., H.K., K.L.R., S.D.W., V.H. and E. Latz wrote the paper. E. Latz conceived and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eicke Latz.

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https://doi.org/10.1038/nature08938

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