| NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. | |
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MedLine Citation:
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PMID: 20428172 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Peter Duewell; Hajime Kono; Katey J Rayner; Cherilyn M Sirois; Gregory Vladimer; Franz G Bauernfeind; George S Abela; Luigi Franchi; Gabriel Nuñez; Max Schnurr; Terje Espevik; Egil Lien; Katherine A Fitzgerald; Kenneth L Rock; Kathryn J Moore; Samuel D Wright; Veit Hornung; Eicke Latz |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 464 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-29 Completed Date: 2010-06-15 Revised Date: 2011-03-21 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 1357-61 Citation Subset: IM |
Affiliation:
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Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atherosclerosis / chemically induced, metabolism*, pathology* Bone Marrow Transplantation Carrier Proteins / genetics, metabolism* Cathepsin B / metabolism Cathepsin L / metabolism Cholesterol / chemistry*, metabolism*, pharmacology Crystallization Cytoskeletal Proteins / deficiency Diet, Atherogenic Female Humans Inflammation / chemically induced, metabolism, pathology Interleukin-1 / deficiency Interleukin-18 / metabolism Lysosomes / drug effects, pathology Mice Mice, Inbred C57BL Peritoneal Cavity / pathology Phagocytes / drug effects, pathology, physiology Receptors, LDL / deficiency Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI075318-03/AI/NIAID NIH HHS; R01 AI083713-01/AI/NIAID NIH HHS; R01 HL093262-01A1/HL/NHLBI NIH HHS; R01 HL093262-03/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CIAS1 protein, mouse; 0/Carrier Proteins; 0/Cytoskeletal Proteins; 0/Interleukin-1; 0/Interleukin-18; 0/Pycard protein, mouse; 0/Receptors, LDL; 57-88-5/Cholesterol; EC 3.4.22.1/Cathepsin B; EC 3.4.22.1/Ctsb protein, mouse; EC 3.4.22.15/Cathepsin L; EC 3.4.22.15/Ctsl protein, mouse |
| Comments/Corrections | |
Erratum In:
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Nature. 2010 Jul 29;466(7306):652 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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