Cited by 1,039Inflammasome and immune disordersAtherosclerosis and Cardiovascular DiseasesCholesterol and Lipid Metabolism

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Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

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Rajamäki, Kristiina, Lappalainen, Jani, Öörni, Katariina, Välimäki, Elina, Matikainen, Sampsa, Kovanen, Petri T., Eklund, Kari K.·2010·PLoS ONE

DOI 10.1371/journal.pone.0011765PMC PMC2909263

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Abstract

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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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: Rajamäki, Kristiina
Lappalainen, Jani
Öörni, Katariina
Matikainen, Sampsa
Kovanen, Petri T.
Eklund, Kari K.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2010-07-23
Volume: 5
Issue: 7
Pages: e11765
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0011765
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
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

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