The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis
Open accessAbstract
Background: The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)–1β reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1β secretion increase cardiovascular risk. IL-1β and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density lipoprotein, and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation. Methods: To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11 . Bone marrow from these mice was transplanted into Ldlr −/− recipients, which were fed a Western-type diet. Results: Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr −/− mice and induced IL-1β and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1 -deficient Ldlr −/− mice. Myeloid Abca1/g1 deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1β and IL-18 levels. Conclusions: Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“induction of cholesterol efflux from myeloid cells inhibits NLRP3 inflammasome activation73.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [73]
In the citing paper
“In myeloid cells in which cholesterol efflux pathways have been genetically suppressed, accumulation of unesterified cholesterol in the cellular membranes without cholesterol crystal formation or lysosomal damage contributes to both priming and activation of the NLRP3 inflammasome73.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [73]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482
A role for mitochondria in nlrp3 inflammasome activation
Zhou, R., Yazdi, A. S., Menu, P., & Tschopp, J. (2011) · Nature · doi:10.1038/nature09663 · Cited by 5,602
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Duewell, P., Kono, H., Rayner, K. J., Sirois, C. M., Vladimer, G., Bauernfeind, F. G., Abela, G. S., Franchi, L., Nuñez, G., Schnurr, M., et al. (2010) · Nature · doi:10.1038/nature08938 · Cited by 4,026
Self-citationMechanisms and Functions of Inflammasomes
Lamkanfi, M., & Dixit, V. M. (2014) · Cell · doi:10.1016/j.cell.2014.04.007 · Cited by 2,579
Non-canonical inflammasome activation targets caspase-11
Kayagaki, N., Warming, S., Lamkanfi, M., Walle, L. V., Louie, S., Dong, J., Newton, K., Qu, Y., Liu, J., Heldens, S., et al. (2011) · Nature · doi:10.1038/nature10558 · Cited by 2,530
Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity
Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., et al. (2012) · Nature · doi:10.1038/nature10809 · Cited by 2,435
Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis
Khera, A. V., Cuchel, M., de la Llera-Moya, M., Rodrigues, A., Burke, M. F., Jafri, K., French, B. C., Phillips, J. A., Mucksavage, M. L., Wilensky, R. L., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1001689 · Cited by 1,943
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
Fuster, J. J., MacLauchlan, S., Zuriaga, M. A., Polackal, M. N., Ostriker, A. C., Chakraborty, R., Wu, C.-L., Sano, S., Muralidharan, S., Rius, C., et al. (2017) · Science · doi:10.1126/science.aag1381 · Cited by 1,536
Cholesterol, inflammation and innate immunity.
Tall, A. R., & Yvan-Charvet, L. (2015) · Nature Reviews Immunology · doi:10.1038/nri3793 · Cited by 1,479
Self-citation
Cited by
Sorted by citations
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
Targeting inflammation in atherosclerosis — from experimental insights to the clinic
Soehnlein, O., & Libby, P. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00198-1 · Cited by 1,085
NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis
Grebe, A., Hoss, F., & Latz, E. (2018) · Circulation Research · doi:10.1161/circresaha.118.311362 · Cited by 926
Neutrophils as regulators of cardiovascular inflammation
Silvestre-Roig, C., Braster, Q., Ortega‐Gómez, A., & Soehnlein, O. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0326-7 · Cited by 627
Metadata
- Authors
- Westerterp, M., Fotakis, P., Ouimet, M., Bochem, A. E., Zhang, H., Molusky, M. M., Wang, W., Abramowicz, S., la Bastide-van Gemert, S., Wang, N., Welch, C. L., Reilly, M. P., Stroes, E. S., Moore, K. J., & Tall, A. R.
- Affiliations
- Division of Molecular Medicine (M.W., P.F., A.E.B., M.M.M., W.W., S.A., N.W., C.L.W., A.R.T.)
- University of Ottawa (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Columbia University Irving Medical Center (US)
- Department of Epidemiology (S.l.B-v.G.), University of Groningen, University Medical Center Groningen, The Netherlands
- NYU Langone Health (US)
- Corresponding author
- Westerterp, Marit
- Fotakis, Panagiotis
- ORCID
- Venue
- Circulation
- Published
- 2018-08-28
- Volume
- 138
- Issue
- 9
- Pages
- 898-912
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6160368
- OpenAlex
- W2795137969
- Cited by
- 331
- References
- 49
- Citations by year
- 2026: 37 · 2025: 40 · 2024: 41 · 2023: 47 · 2022: 45 · 2021: 45 · 2020: 36 · 2019: 28 · 2018: 11
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- University of Ottawa
- York University
- Rijksuniversiteit Groningen
- Universiteit van Amsterdam
- Universitair Medisch Centrum Groningen
- National Institutes of Health
- National Heart, Lung, and Blood Institute (K24HL107643, R01HL113147, R01HL117334, R35HL135799, K99HL130574, R01HL107653, T32HL007343)
- National Center for Research Resources (S10RR027050)
- 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 efflux, ABCA1, ABCG1, NLRP3 inflammasome, caspase-1, caspase-11, IL-1β, IL-18, NETosis, atherogenesis, myeloid cells, non-canonical inflammasome, Tangier disease
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cholesterol, Disease Models, Animal, Humans, Inflammation, Receptors, LDL, Spleen, Tangier Disease, Case-Control Studies, Cytokines, Mice, Knockout, Caspases, Caspase 1, Myeloid Cells, Atherosclerosis, Caspases, Initiator, Plaque, Atherosclerotic, Inflammasomes, ATP Binding Cassette Transporter 1, Extracellular Traps
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
