NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Nature (Impact Factor: 41.46). 04/2010; 464(7293):1357-61. DOI: 10.1038/nature08938


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 inflammation. 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) inflammasome, 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-1alpha/beta-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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    • "About four decades ago, virus-induced cholesterol crystals were observed in cultured cells, and such crystals are known to form when cholesterol accumulates in the plaque and to activate inflammasomes (Fabricant et al., 1973; Duewell et al., 2010). Moreover viral infection was shown to induce experimental atherosclerosis and also to alter aortic cholesterol metabolism and accumulation (Fabricant et al., 1978; Hajjar et al., 1986). "
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    • "In addition, there is ample evidence of inflammasome activation in atherosclerotic lesions, and IL-1 likely plays an important role in early atherogenesis (Lu and Kakkar, 2014). Based on in vitro studies and in vivo observations, a leading hypothesis posits that cholesterol microcrystals derived from the cellular ingestion of retained LPs activate the inflammasome pathway (Duewell et al., 2010). However, it is not clear whether cholesterol crystallization would be robust enough at body temperature to activate the inflammasome pathway, and so other mechanisms of are being explored. "
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