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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

A Corrigendum to this article was published on 29 July 2010


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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Figure 1: Cholesterol crystals appear in early atherosclerotic lesions.
Figure 2: Cholesterol crystals activate the NLRP3 inflammasome.
Figure 3: Cholesterol crystals activate the NLRP3 inflammasome by inducing lysosomal damage.
Figure 4: The NLRP3 inflammasome mediates crystal-induced peritoneal inflammation and atherosclerosis in vivo.


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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.).

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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.

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Correspondence to Eicke Latz.

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The authors declare no competing financial interests.

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

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