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Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation
Open accessAbstract
BACKGROUND: Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway. PRINCIPAL FINDINGS: Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization. CONCLUSIONS: The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
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“Primed macrophages secrete large amounts of IL‐1β in response to cholesterol crystals in an NLRP3 inflammasome‐dependent manner in mouse and human cells.34, 35”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [34]
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Metadata
- Authors
- Rajamäki, K., Lappalainen, J., Öörni, K., Välimäki, E., Matikainen, S., Kovanen, P. T., & Eklund, K. K.
- Affiliations
- Wihuri Research Institute (FI)
- Finnish Institute of Occupational Health (FI)
- Corresponding author
- Rajamäki, Kristiina
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-07-23
- Volume
- 5
- Issue
- 7
- Pages
- e11765
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2909263
- OpenAlex
- W2028545985
- Semantic Scholar
- fa6cd20e147dd066a3358c77aa3fc9b4dc9ff451
- Cited by
- 1,039
- References
- 60
- Citations by year
- 2026: 65 · 2025: 51 · 2024: 45 · 2023: 77 · 2022: 80 · 2021: 74 · 2020: 72 · 2019: 57 · 2018: 66 · 2017: 77 · 2016: 52 · 2015: 76 · 2014: 75 · 2013: 70 · 2012: 59
- FWCI
- 21.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Jenny ja Antti Wihurin Rahasto
- 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
- cholesterol crystals, NLRP3 inflammasome, macrophages, atherosclerosis, IL-1β secretion, caspase-1, lysosomal destabilization, cathepsin B, cholesterol esters, cholesterol metabolism, inflammation, monocytes
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Carrier Proteins, Cathepsin B, Cells, Cultured, Cholesterol, Chromatography, Thin Layer, Cytoplasm, Humans, Inflammation, Lipopolysaccharides, Lysosomes, Macrophages, Monocytes, Phagocytosis, Potassium, Blotting, Western, Cytochalasin D, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Caspase 1, RNA, Small Interfering, Interleukin-1beta, Caspase Inhibitors
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