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NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice—Brief Report
Open accessAbstract
Objective—: Inflammasomes are multiprotein complexes, and their activation has been associated with cardiovascular disease. Inflammasome activation leads to secretion of caspase-1 by innate immune cells, resulting in the activation of interleukin-1β. Recently, a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, was described. In this study, we investigated the effect of MCC950 on atherosclerotic lesion development in apoE −/− mice. Approach and Results—: First, we determined the efficacy of MCC950 in vitro. Bone marrow–derived macrophages and dendritic cells were stimulated with lipopolysaccharide and cholesterol crystals resulting in high levels of interleukin-1β release, which was inhibited by MCC950. In vivo MCC950 treatment reduced lipopolysaccharide–induced interleukin-1β secretion, without affecting the tumor necrosis factor-α response. Subsequently, atherosclerotic plaques were induced in Western-type diet fed apoE −/− mice by semiconstrictive perivascular collar placement at the carotid arteries, after which the mice received MCC950 (10 mg/kg) or vehicle control 3× per week intraperitoneally for 4 weeks. After euthanize, atherosclerotic plaque size and volume were quantified in hematoxylin-eosin–stained 10-µm cryosections throughout the artery. MCC950 treatment significantly reduced the development of atherosclerotic lesions as determined by maximal stenosis, average plaque size, and plaque volume. Although the amount of collagen and the necrotic core size were not affected, the number of macrophages in the plaque was significantly reduced on treatment. In addition, VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA expression was significantly reduced in the carotids of MCC950-treated mice. Conclusions—: These findings show that specific inhibition of the NLRP3 inflammasome using MCC950 can be a promising therapeutic approach to inhibit atherosclerotic lesion development.
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“In a mouse model of atherosclerosis, the inhibition of the NLRP3 inflammasome by MCC950 resulted in a significant reduction in atherosclerotic lesions [82].”
From Neuroprotective effect of SGLT2 inhibitors. (2021) · cites this paper as [82]
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“Inhibition of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome (NLRP3) suppressed T-cell senescence57 and atherosclerosis.58”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [58]
In the citing paper
“Human atherosclerotic lesions show increased expression of the major components of NLRP3 (REF 61), and inhibition of the NLRP3 inflammasome reduces atherosclerosis in Apoe−/− mice62.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [62]
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Cites
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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
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Lack of Interleukin-1β Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice
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IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation
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The NLRP3 inflammasome: molecular activation and regulation to therapeutics
Swanson, K. V., Deng, M., & Ting, J. P.-Y. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0165-0 · Cited by 4,884
Targeting the NLRP3 inflammasome in inflammatory diseases
Mangan, M. S. J., Olhava, E. J., Roush, W. R., Seidel, H. M., Glick, G. D., & Latz, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.97 · Cited by 1,885
Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities
Bäck, M., Yurdagul, A., Tabas, I., Öörni, K., & Kovanen, P. T. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0169-2 · Cited by 1,341
Inflammation and atherosclerosis: signaling pathways and therapeutic intervention
Kong, P., Cui, Z.-Y., Huang, X.-F., Zhang, D.-D., Guo, R.-J., & Han, M. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00955-7 · Cited by 1,183
Xu, S., Ilyas, I., Little, P. J., Li, H., Kamato, D., Zheng, X., Luo, S., Li, Z., Liu, P., Han, J., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000096 · Cited by 1,205
Metadata
- Authors
- van der Heijden, T., Kritikou, E., Venema, W., van Duijn, J., van Santbrink, P. J., Slütter, B., Foks, A. C., Bot, I., & Kuiper, J.
- Affiliations
- From the Cluster BioTherapeutics, LACDR, Leiden University, The Netherlands.
- Leiden University (NL)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2017-08
- Volume
- 37
- Issue
- 8
- Pages
- 1457-1461
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2623847043
- Cited by
- 348
- References
- 21
- Citations by year
- 2026: 25 · 2025: 28 · 2024: 35 · 2023: 49 · 2022: 47 · 2021: 66 · 2020: 40 · 2019: 29 · 2018: 24 · 2017: 4
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- European Commission
- ZonMw
- Servier
- Nederlandse Federatie van Universitair Medische Centra
- 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, MCC950, atherosclerosis, atherosclerotic plaque, ApoE-deficient mice, IL-1β, caspase-1, macrophages, dendritic cells, VCAM-1, ICAM-1, carotid artery stenosis, anti-inflammatory therapy
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Anti-Inflammatory Agents, Apolipoproteins E, Carotid Arteries, Carotid Artery Diseases, Cells, Cultured, Cholesterol, Crystallization, Dendritic Cells, Disease Models, Animal, Female, Furans, Heterocyclic Compounds, 4 or More Rings, Indenes, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Necrosis, Phenotype, RNA, Messenger, Sulfonamides, Sulfones, Time Factors, Signal Transduction, Mice, Knockout, Intercellular Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, Genetic Predisposition to Disease, Atherosclerosis, Interleukin-1beta, Plaque, Atherosclerotic, Inflammasomes, Diet, Western
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