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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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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 measuredIn the citing paper
“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]
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
“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]
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]
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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From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk
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The role of the NLRP3 inflammasome in gout
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“76,77 Late-stage human melanoma cells exhibit autoinflammatory characteristics, spontaneously secreting active IL-1 β due to constitutive assembly and activation of NLRP3.”
Crystal nephropathies: mechanisms of crystal-induced kidney injury
Mulay, S. R., & Anders, H. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.10 · Cited by 227
Therapeutic modulation of inflammasome pathways
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Histones Activate the NLRP3 Inflammasome in Kupffer Cells during Sterile Inflammatory Liver Injury
Huang, H., Chen, H., Evankovich, J. W., Yan, W., Rosborough, B. R., Nace, G., Ding, Q., Loughran, P., Beer–Stolz, D., Billiar, T. R., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202733 · Cited by 217
Diversity of macrophage phenotypes and responses in atherosclerosis
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“Recent studies using NLRP3 inflammasome knockout mice have shown that the NLRP3 inflammasome controls the pathogenesis of type II diabetes mellitus (Wen et al., 2011), atherosclerosis (Duewell et al., 2010), Alzheimer’s disease (Halle et al., 2008.)”
BackgroundSharma, A., Tate, M., Mathew, G., Vince, J. E., Ritchie, R. H., & de Haan, J. B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00114 · Cited by 221
“…with bone marrow from either NLRP3-, ASC, IL-1α/β or caspase 1/11-deficient mice are protected from the development of diet-induced atherosclerosis (Duewell et al., 2010; Hendrikx et al., 2015), further strengthening the role of myeloid-cell derived NLRP3, ASC, caspase-1 and IL-1β in the…”
BackgroundInfluentialThe NLR gene family: from discovery to present day
Chou, W.-C., Jha, S., Linhoff, M. W., & Ting, J. P. ‐. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00849-x · Cited by 232
“However, NLRP3 can be activated by many diverse pathways, including through the chemical disruption of glycolysis 88 or by cellular accumulation of cholesterol crystals 89 or free fatty acids 90 .”
BackgroundDanger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders
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IL ‐1β and IL ‐18: inflammatory markers or mediators of hypertension?
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Obesity and Atherosclerosis: Mechanistic Insights
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The Lysosome Rupture-activated TAK1-JNK Pathway Regulates NLRP3 Inflammasome Activation
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Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis
Mistry, P., & Kaplan, M. J. (2016) · Clinical Immunology · doi:10.1016/j.clim.2016.08.010 · Cited by 215
Clonal haematopoiesis and risk of chronic liver disease
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Mechanistic insights from inflammasome structures
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“Crystals and particles that activate NLRP3 include monosodium urate crystals 13 , aluminium hydroxide, silica, asbestos 121,122 , cholesterol crystals 123,124 and amyloid-β (ref.”
The NLR family of innate immune and cell death sensors
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Processes of Sterile Inflammation
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Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants
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Early Hyperlipidemia Promotes Endothelial Activation via a Caspase-1-Sirtuin 1 Pathway
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“The activated NALP3 inflammasome contributes to antifungal host defense, antitumor immunity, and inflammation (Duewell et al., 2010; Ghiringhelli et al., 2009; Gross et al., 2009; Halle et al., 2008; Watanabe et al., 2008).”
Guan, B., Tong, J., Hao, H., Yang, Z., Chen, K., Xu, H., & Wang, A. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.12.011 · Cited by 215
Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets
Meyer, G. R. Y. D., Zurek, M., Puylaert, P., & Martinet, W. (2024) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00957-0 · Cited by 221
“Atherosclerotic plaques in Ldlr –/– mice with NLRP3-deficient or IL-1-deficient bone marrow are nearly 70% smaller compared with plaques in control animals ( Ldlr –/– with wild-type bone marrow) 65 .”
Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R., & Clarke, M. C. H. (2013) · Immunity · doi:10.1016/j.immuni.2013.01.008 · Cited by 205
“Indeed, increased IL-1 activity is a hallmark of many chronic inflammatory conditions, including rheumatoid arthritis, gout, diabetes, atherosclerosis, and psoriasis (Dinarello, 1996, 2009; Duewell et al., 2010; Rajamäki et al., 2010).”
Dynamic Aspects of Macrophage Polarization during Atherosclerosis Progression and Regression
Peled, M., & Fisher, E. A. A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00579 · Cited by 212
New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease
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Self-citationMitochondria and the NLRP3 inflammasome: physiological and pathological relevance
Yu, J., & Lee, M. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0827-4 · Cited by 209
Toll-like receptor (TLR) and inflammasome actions in the central nervous system
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Adipose tissue inflammation and ectopic lipid accumulation [Review]
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Immunotherapy for cardiovascular disease
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HIV-1 tat primes and activates microglial NLRP3 inflammasome-mediated neuroinflammation.
Chivero, E. T., Guo, M.-L., Periyasamy, P., Liao, K., Callen, S. E., & Buch, S. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3045-16.2017 · Cited by 201
“…release of IL-1 , microglia primed by Tat could become more sensitive to the effects of other proinflammatory factors previously described as NLRP3 activators such as lipotoxic fatty acids, ceramides, and free cholesterol (Duewell et al., 2010; Vandanmagsar et al., 2011; Wen et al., 2011).”
Background
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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