Show simple item record

dc.contributor.authorDuewell, Peter
dc.contributor.authorKono, Hajime
dc.contributor.authorRayner, Katey J.
dc.contributor.authorSirois, Cherilyn M.
dc.contributor.authorVladimer, Gregory
dc.contributor.authorBauernfeind, Franz G.
dc.contributor.authorAbela, George S.
dc.contributor.authorFranchi, Luigi
dc.contributor.authorNuñez, Gabriel
dc.contributor.authorSchnurr, Max
dc.contributor.authorEspevik, Terje
dc.contributor.authorLien, Egil
dc.contributor.authorFitzgerald, Katherine A.
dc.contributor.authorRock, Kenneth L.
dc.contributor.authorMoore, Kathryn J.
dc.contributor.authorWright, Samuel D.
dc.contributor.authorHornung, Veit
dc.contributor.authorLatz, Eicke
dc.date2022-08-11T08:08:53.000
dc.date.accessioned2022-08-23T16:11:13Z
dc.date.available2022-08-23T16:11:13Z
dc.date.issued2010-04-29
dc.date.submitted2010-09-15
dc.identifier.citation<p>Nature. 2010 Apr 29;464(7293):1357-61.</p>
dc.identifier.issn1476-4687
dc.identifier.doi10.1038/nature08938
dc.identifier.pmid20428172
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33112
dc.description.abstractThe 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.
dc.language.isoen_US
dc.publisherNature Publishing Group
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20428172&dopt=Abstract">Link to article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946640/
dc.subjectAnimals; Atherosclerosis; Bone Marrow Transplantation; Carrier Proteins; Cathepsin B; Cathepsin L; Cholesterol; Crystallization; Cytoskeletal Proteins; Diet, Atherogenic; Female; Humans; Inflammation; Interleukin-1; Interleukin-18; Lysosomes; Mice; Mice, Inbred C57BL; Peritoneal Cavity; Phagocytes; Receptors, LDL; Time Factors
dc.subjectCell Biology
dc.subjectImmunology and Infectious Disease
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleNLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
dc.typeJournal Article
dc.source.journaltitleNature
dc.source.volume464
dc.source.issue7293
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/1655
dc.identifier.contextkey1558858
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_sp/1655
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.contributor.studentCherilyn M. Sirois; Gregory Vladimer


This item appears in the following Collection(s)

Show simple item record