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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Open accessAbstract
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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“Oxidized low‐density lipoprotein and cholesterol crystals activate the inflammasome, thereby leading to the processing and secretion of the proinflammatory cytokines IL‐1β and IL‐18 and ultimately triggering vascular inflammation via upregulation of adhesion molecules.9, 10”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Urate and cholesterol crystals, as well as sterile particulates, for example, can bypass the requirement for ATP and P2RX7 for IL-1β production55,59.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“For these sterile particulates to activate NLRP3, they must be internalized, as blockade of endocytosis by the actin-depolymerizing drug cytochalasin D inhibited NLRP3-dependent IL-1β production58,59.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
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In the citing paper
“Oxidized low-density lipoprotein (LDsL), a cholesterol carrier, can also form crystals within lysosomes after internalization [74].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [74]
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In the citing paper
“Elevation of CEs and BMPs was also observed in LOAD patients’ EC, suggesting disease relevance.43”
From Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist (2024) · cites this paper as [44]
Experimental — accuracy not yet measured
In the citing paper
“AS is decreased in several rodent models lacking NLRP3 or IL‐1 molecules, whereas in contrast, mice deficient in the IL‐1 receptor antagonist show increased AS.10”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [10]
In the citing paper
“These results clearly indicate that the NLRP3 inflammasome plays a key role in the pathogenesis of vascular inflammation, thereby contributing to AS development.”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [10]
In the citing paper
“Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses.”
From Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages (2018) · cites this paper as [20]
In the citing paper
“The NLRP3 inflammasome senses crystalline danger signals that can occur during autoinflammatory diseases, such as gout or atherosclerosis, and environmental diseases, such as silicosis or asbestosis (18, 20, 22).”
From Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages (2018) · cites this paper as [20]
In the citing paper
“inflammasome-dependent cytokine synthesis and release is a two-step process that is initiated after ligation of TLRs and other receptors capable of binding DAMPS and/or MAMPs leading to NLRP3 gene transcription, translation, and protein production (Duewell et al, 2010).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Duewell et al, 2010
In the citing paper
“Low-density lipoprotein (LDL) receptor-deficient mice, which are prone to developing atherosclerotic lesions, had lower IL-1β levels, smaller atherosclerotic lesions and less neutrophilic infiltration than wild-type mice when lethally irradiated and infused with NLRP3-deficient bone marrow59.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
In the citing paper
“Lysosomal damage can occur during cellular injury and necrosis, and has also been associated with other sterile activators of NLRP3, such as cholesterol59 and silica crystals44.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
In the citing paper
“However, cathepsin b-deficient macrophages have no impairment in IL-1β production in response to certain NLRP3 agonists, including LPS plus ATP, or MSU crystals, despite the impairment in their response to silica44,56,59,67.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
In the citing paper
“Furthermore, there is only partial inhibition of the neutrophil infiltration and IL-1β production associated with sterile inflammation in response to cholesterol crystals44,56,59,67.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
In the citing paper
“evidence to support this are the observations that artificial lysosomal rupture alone can activate NLRP3 and that pharmacological inhibition or genetic depletion of cathepsin b results in inhibition of caspase 1 activation, although this inhibition was only partial44,56,59.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [59]
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Chae, J. J., Park, Y. H., Park, C., Hwang, I., Hoffmann, P., Kehrl, J. H., Aksentijevich, I., & Kastner, D. L. (2015) · Arthritis & Rheumatology · doi:10.1002/art.38961 · Cited by 89
Gout as autoinflammatory disease: New mechanisms for more appropriated treatment targets
Punzi, L., Scanu, A., Ramonda, R., & Oliviero, F. (2012) · Autoimmunity Reviews · doi:10.1016/j.autrev.2012.07.024 · Cited by 90
Wu, Z., Sun, L., Hashioka, S., Yu, S., Schwab, C., Okada, R., Hayashi, Y., McGeer, P. L., & Nakanishi, H. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.05.018 · Cited by 91
The role of mitochondrial DNA damage in the development of atherosclerosis
Yu, E., & Bennett, M. R. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.06.011 · Cited by 92
Gut Microbiota and Atherosclerosis
Li, D. Y., & Tang, W. H. W. (2017) · Current Atherosclerosis Reports · doi:10.1007/s11883-017-0675-9 · Cited by 90
Wang, R., Wu, W., Li, W., Huang, S., Li, Z., Liu, R.-M., Shan, Z., Zhang, C., Li, W., & Wang, S. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.118.008596 · Cited by 89
Corrêa, R., Silva, L. F. F., Ribeiro, D. J. S., Almeida, R. D. N., Santos, I. D. O., Corrêa, L. H., de Sant’Ana, L. P., Assunção, L. S., Bozza, P. T., & Magalhães, K. G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02927 · Cited by 93
Inflammation and Cardiovascular Disease: The Future
Arnold, N., Lechner, K., Waldeyer, C., Shapiro, M. D., & Köenig, W. (2021) · European Cardiology Review · doi:10.15420/ecr.2020.50 · Cited by 93
Thromboinflammation: From Atherosclerosis to COVID-19
Wagner, D. D., & Heger, L. A. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317162 · Cited by 95
Trapping of oxidized LDL in lysosomes of K upffer cells is a trigger for hepatic inflammation
Bieghs, V., Walenbergh, S. M. A., Hendrikx, T., van Gorp, P. J., Verheyen, F., Damink, S. W. M. O., Masclee, A., Koek, G. H., Hofker, M. H., Binder, C. J., et al. (2013) · Liver International · doi:10.1111/liv.12170 · Cited by 88
The inflammasome: in memory of Dr. Jurg Tschopp
Dagenais, M., Skeldon, A. M., & Saleh, M. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.159 · Cited by 92
Genipin inhibits NLRP3 and NLRC4 inflammasome activation via autophagy suppression
Yu, S.-X., Du, C., Chen, W., Lei, Q.-Q., Li, N., Qi, S., Zhang, X.-J., Hu, G., Deng, X., Han, W., et al. (2015) · Scientific Reports · doi:10.1038/srep17935 · Cited by 86
Mohamed, I., Ishrat, T., Fagan, S. C., & El‐Remessy, A. B. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6126 · Cited by 88
Tumurkhuu, G., Dagvadorj, J., Porritt, R. A., Crother, T. R., Shimada, K., Tarling, E. J., Erbay, E., Arditi, M., & Chen, S. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.027 · Cited by 89
XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1β-mediated diseases
Owyang, A. M., Issafras, H., Corbin, J., Ahluwalia, K., Larsen, P., Pongo, E., Handa, M., Horwitz, A. H., Roell, M. K., Haak‐Frendscho, M., et al. (2011) · mAbs · doi:10.4161/mabs.3.1.13989 · Cited by 89
IL-1 family cytokines in cardiovascular disease
Pfeiler, S., Winkels, H., Kelm, M., & Gerdes, N. (2017) · Cytokine · doi:10.1016/j.cyto.2017.11.009 · Cited by 88
Epigenetic Mechanisms of Inflammasome Regulation
Poli, G., Fabi, C., Bellet, M. M., Costantini, C., Nunziangeli, L., Romani, L. R., & Brancorsini, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165758 · Cited by 87
“Its role has been characterized first in a subset of rare autoinflammatory conditions [18] and, subsequently, in inflammatory [19–23] and metabolic diseases [24].”
BackgroundLipid scavenging macrophages and inflammation
Vogel, A., Brunner, J. S., Hajto, A., Sharif, O., & Schabbauer, G. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.159066 · Cited by 92
Innate immune sensing of cell death in disease and therapeutics
Man, S. M., & Kanneganti, T. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01491-y · Cited by 94
“NLRP3 is highly responsive to lytic dead cell corpses 82 and DAMPs associated with cell death, notably ATP 19–22 , β-amyloids 83,84 , biglycan 85 , endogenous crystals 86,87 , free fatty acids 88 , histones 89 , mitochondrial DNA 90–92 , RNA 93,94 , and S100A8 or S100A9 (ref.”
Cellular and molecular choreography of neutrophil recruitment to sites of sterile inflammation
McDonald, B., & Kubes, P. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0784-9 · Cited by 93
Zhang, A., Wang, P., Ma, X., Yin, X., Li, J., Wang, H., Jiang, W., Jia, Q., & Ni, L. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.03.009 · Cited by 87
Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease
Swaminathan, S., & Shah, S. V. (2011) · Kidney International · doi:10.1038/ki.2011.178 · Cited by 86
Sevenich, L., Werner, F., Gajda, M., Schurigt, U., Sieber, C., Müller, S., Follo, M., Peters, C., & Reinheckel, T. (2011) · Oncogene · doi:10.1038/onc.2010.387 · Cited by 85
“It is noteworthy that cathepsin B has been implicated in IL-1b processing during inflammasome activation under distinct pathological conditions by mechanisms that require lysosomal damage to release cathepsin B into the cytosol to cleave IL-1b (Halle et al., 2008; Duewell et al., 2010).”
Lipid and Non-lipid Factors Affecting Macrophage Dysfunction and Inflammation in Atherosclerosis
Gibson, M. S., Domingues, N. S., & Vieira, O. V. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00654 · Cited by 82
Immunometabolic function of cholesterol in cardiovascular disease and beyond
Yvan‐Charvet, L., Bonacina, F., Guinamard, R., & Norata, G. D. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz127 · Cited by 89
“(oxLDL) uptake inhibits subsequent hydrolysis of lipoprotein particles.(71,75,76) Macrophage NPC1 deficiency also promoted cholesterol accumulation(77) but the inflammatory response was rather associated with activation of TLR3 signalling due to modulation of late ELC cholesterol accumulation.”
BackgroundWu, L., Wu, S.-G., Chen, F., Wu, Q., Wu, C.-M., Kang, C., He, X., Zhang, R., Lu, Z.-F., Li, X.-H., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.11.033 · Cited by 86
Jin, X., Yang, S., Lu, J., & Wu, M. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.804214 · Cited by 86
Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury.
Chen, Y., Guo, X., Xiao, L., Wei, J., Luo, J., Chen, G.-N., Yan, X., Wen, X., Zhong, M., & Lv, X. (2016) · PubMed Central · Cited by 86
Interaction between periodontal disease and atherosclerotic vascular disease – Fact or fiction?
Aarabi, G., Eberhard, J., Reissmann, D. R., Heydecke, G., & Seedorf, U. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.04.819 · Cited by 88
Org, E., Mehrabian, M., & Lusis, A. J. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.05.035 · Cited by 85
Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?
Ridker, P. M. (2012) · Current Atherosclerosis Reports · doi:10.1007/s11883-012-0295-3 · Cited by 86
Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis
Onat, U. İ., Yıldırım, A., Tufanlı, Ö., Çimen, İ., Kocatürk, B., Veli, Z., Hamid, S. M., Shimada, K., Chen, S., Sin, J., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.12.055 · Cited by 84
NLRP3 inflammasome as a treatment target in atherosclerosis: A focus on statin therapy
Parsamanesh, N., Moossavi, M., Bahrami, A., Fereidouni, M., Barreto, G. E., & Sahebkar, A. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.05.006 · Cited by 87
Clinical approach to the inflammatory etiology of cardiovascular diseases
Ruscica, M., Corsini, A., Ferri, N., Banach, M., & Sirtori, C. R. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104916 · Cited by 87
“Cholesterol itself is an inflammatory mediator, being a crystalline product [1] and, by its physical presence, activating NLRP3 (NACHT-, LRR- and pyrin domain-containing 3), a general mediator of arterial tissue inflammation [2].”
Role of Extracellular Vesicles in Cell Death and Inflammation
Sanwlani, R., & Gangoda, L. (2021) · Cells · doi:10.3390/cells10102663 · Cited by 90
“Another form of cell death known as pyroptosis has been long studied for its role in chronic inflammatory diseases, such as Alzheimer’s disease [87,88] and atherosclerosis [89].”
BackgroundLymphocyte Migration Into Atherosclerotic Plaque
Li, J., & Ley, K. F. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.303227 · Cited by 89
“Within the vessel wall, crystallization of cholesterol and oxidation of low-density lipoprotein (LDL) result in cellactivating proinflammatory signals, which stimulate both innate and adaptive chronic inflammatory responses in the arterial intima.(2,3) The innate immune system initiates the recruitment of monocytes fr…”
Dı́az-Araya, G., Vivar, R., Humeres, C. D., Boza, P., Bolívar, S., & Muñoz, C. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.07.001 · Cited by 87
Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury
Tan, X., Zheng, X., Huang, Z., Jiaqiong, L., Xie, C., & Lin, Y. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000480340 · Cited by 84
Suciu, C. F., Prete, M., Ruscitti, P., Favoino, E., Giacomelli, R., & Perosa, F. (2018) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.11.028 · Cited by 84
Highlighting Residual Atherosclerotic Cardiovascular Disease Risk
Matsuura, Y., Kanter, J. E., & Bornfeldt, K. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311999 · Cited by 88
Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke
Feng, Y.-S., Tan, Z., Wang, M., Xing, Y., Dong, F., & Zhang, F. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00155 · Cited by 85
Metadata
- Authors
- Duewell, P., Kono, H., Rayner, K. J., Sirois, C. M., Vladimer, G., Bauernfeind, F. G., Abela, G. S., Franchi, L., Nuñez, G., Schnurr, M., Espevik, T., Lien, E., Fitzgerald, K. A., Rock, K. L., Moore, K. J., Wright, S. D., Hornung, V., & Latz, E.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Harvard University (US)
- Michigan State University (US)
- University of Michigan (US)
- Ludwig-Maximilians-Universität München (DE)
- Norwegian University of Science and Technology (NO)
- CSL (Australia) (AU)
- University of Bonn (DE)
- Corresponding author
- Latz, Eicke
- ORCID
- Venue
- Nature
- Published
- 2010-04-01
- Volume
- 464
- Issue
- 7293
- Pages
- 1357-1361
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2946640
- OpenAlex
- W1972483153
- Cited by
- 4,026
- References
- 31
- Citations by year
- 2026: 274 · 2025: 255 · 2024: 291 · 2023: 299 · 2022: 321 · 2021: 307 · 2020: 291 · 2019: 270 · 2018: 282 · 2017: 245 · 2016: 199 · 2015: 228 · 2014: 194 · 2013: 197 · 2012: 197
- FWCI
- 72.42
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-07-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL093262)
- National Institute of Allergy and Infectious Diseases (R01AI075318, R01AI083713)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- NLRP3 inflammasome, cholesterol crystals, atherogenesis, atherosclerosis, phagocytes, IL-1β, IL-1α, cathepsin B, cathepsin L, ASC, caspase-1, LDL receptor, apolipoprotein E deficiency, high-cholesterol diet
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Cathepsin B, Cholesterol, Crystallization, Cytoskeletal Proteins, Diet, Atherogenic, Female, Humans, Inflammation, Interleukin-1, Lysosomes, Mice, Inbred C57BL, Peritoneal Cavity, Phagocytes, Receptors, LDL, Time Factors, Bone Marrow Transplantation, Interleukin-18, Atherosclerosis, Apoptosis Regulatory Proteins, Mice, CARD Signaling Adaptor Proteins, Cathepsin L
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