Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation
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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.
“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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Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Gout-associated uric acid crystals activate the NALP3 inflammasome
Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., & Tschopp, J. (2006) · Nature · doi:10.1038/nature04516 · Cited by 5,326 · see citing works
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 · cited 1× · see citing works
“While this study was being finalized, Duewell and colleagues published a similar study reporting that cholesterol crystals activate the NLRP3 inflammasome in mouse macrophages through a lysosomal damage- and cathepsin-mediated mechanism”
BackgroundCryopyrin activates the inflammasome in response to toxins and ATP
Mariathasan, S., Weiss, D. S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W. P., Weinrauch, Y., Monack, D. M., & Dixit, V. M. (2006) · Nature · doi:10.1038/nature04515 · Cited by 3,080 · see citing works
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., & Latz, E. (2008) · Nature Immunology · doi:10.1038/ni.1631 · Cited by 3,065 · see citing works
Bauernfeind, F. G., Horvath, G. L., Stutz, A., Alnemri, E. S., MacDonald, K. L., Speert, D. P., Fernandes‐Alnemri, T., Wu, J., Monks, B. G., Fitzgerald, K. A., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901363 · Cited by 3,006 · see citing works
Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Dostert, C., Pétrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008) · Science · doi:10.1126/science.1156995 · Cited by 2,658 · see citing works
The Inflammasomes: Guardians of the Body
Martinon, F., Mayor, A., & Tschopp, J. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132715 · Cited by 2,436 · see citing works
NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?
Tschopp, J., & Schroder, K. (2010) · Nature reviews. Immunology · doi:10.1038/nri2725 · Cited by 1,859 · see citing works
Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways
Tedgui, A., & Mallat, Z. (2006) · Physiological Reviews · doi:10.1152/physrev.00024.2005 · Cited by 1,701 · see citing works
Ohashi, K., Burkart, V., Flohé, S. B., & Kolb, H. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.2.558 · Cited by 1,607 · see citing works
Immune and Inflammatory Mechanisms of Atherosclerosis
Galkina, E., & Ley, K. F. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132620 · Cited by 1,446 · see citing works
Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration
Pétrilli, V, Papin, S., Dostert, C., Mayor, A., Martinon, F., & Tschopp, J. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402195 · Cited by 1,445 · see citing works
The Extra Domain A of Fibronectin Activates Toll-like Receptor 4
Okamura, Y., Watari, M., Jerud, E. S., Young, D. W., Ishizaka, S. T., Rose, J., Chow, J. C., & Strauss, J. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100099200 · Cited by 1,217 · see citing works
Michelsen, K. S., Wong, M. H., Shah, P. K., Zhang, W., Yano, J., Doherty, T. M., Akira, S., Rajavashisth, T. B., & Arditi, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403249101 · Cited by 1,019 · see citing works
The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response
Muruve, D. A., Pétrilli, V., Zaiss, A. K., White, L. R., Clark, S. A., Ross, P. J., Parks, R. J., & Tschopp, J. (2008) · Nature · doi:10.1038/nature06664 · Cited by 936 · see citing works
Lack of Interleukin-1β Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice
Kirii, H., Niwa, T., Yamada, Y., Wada, H., Saito, K., Iwakura, Y., Asano, M., Moriwaki, H., & Seishima, M. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000064374.15232.c3 · Cited by 748 · see citing works
Geng, Y., & Libby, P. (1995) · PubMed · Cited by 641 · see citing works
Kol, A., Lichtman, A. H., Finberg, R. W., Libby, P., & Kurt‐Jones, E. A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.1.13 · Cited by 554 · see citing works
Interleukin‐1β, Interleukin‐18, and the Interleukin‐1β Converting Enzymea
Dinarello, C. A. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb08307.x · Cited by 497 · see citing works
The inflammasomes: mechanisms of activation and function
Latz, E. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.12.004 · Cited by 455 · see citing works
The cell surface receptors for interleukin-1α and interleukin-1β are identical
Dower, S., Kronheim, S. R., Hopp, T. P., Cantrell, M., Deeley, M. C., Gillis, S. A., Henney, C. S., & Urdal, D. L. (1986) · Nature · doi:10.1038/324266a0 · Cited by 415 · see citing works
Katz, S. S., Shipley, G. G., & SMALL, D. M. (1976) · Journal of Clinical Investigation · doi:10.1172/jci108450 · Cited by 349 · see citing works
In Vivo Imaging of Proteolytic Activity in Atherosclerosis
Chen, J., Tung, C., Mahmood, U., Ntziachristos, V., Gyurko, R., Fishman, M. C., Huang, P. L., & Weissleder, R. (2002) · Circulation · doi:10.1161/01.cir.0000017860.20619.23 · Cited by 349 · see citing works
Interleukin-1β in Coronary Arteries of Patients With Ischemic Heart Disease
Galea, J., Armstrong, J., Gadsdon, P., Holden, H. M., Francis, S., & Holt, C. M. (1996) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.16.8.1000 · Cited by 310 · see citing works
Mechanical properties of model atherosclerotic lesion lipid pools.
Loree, H., Tobias, B. J., Gibson, L. J., Kamm, R., Small, D., & Lee, R. T. (1994) · Arteriosclerosis and Thrombosis A Journal of Vascular Biology · doi:10.1161/01.atv.14.2.230 · Cited by 294 · see citing works
Miller, Y. I., Viriyakosol, S., Worrall, D. S., Boullier, A., Butler, S. S., & Witztum, J. L. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000159891.73193.31 · Cited by 279 · see citing works
Novel epoxysuccinyl peptides Selective inhibitors of cathepsin B, in vitro
Murata, M., Miyashita, S., Yokoo, C., Tamai, M., Hanada, K., HATAYAMA, K., Towatari, T., Nikawa, T., & Katunuma, N. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)80318-w · Cited by 273 · see citing works
Hazuda, D. J., Lee, J. C., & Young, P. R. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68502-3 · Cited by 262 · see citing works
Liu, J., Sukhova, G. K., Yang, J.-T., Sun, J., Ma, L., An, R., Xu, W.-H., Fu, H., Dolganov, G., Hu, C., et al. (2005) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2005.05.012 · Cited by 223 · see citing works
Novel epoxysuccinyl peptides A selective inhibitor of cathepsin B, in vivo
Towatari, T., Nikawa, T., Murata, M., Yokoo, C., Tamai, M., Hanada, K., & Katunuma, N. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)80319-x · Cited by 220 · see citing works
Abela, G. S., Aziz, K. S., Vedre, A., Pathak, D. R., Talbott, J. D., & deJong, J. L. (2009) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2008.12.019 · Cited by 214 · see citing works
Human pro-IL-1 beta gene expression in monocytic cells is regulated by two distinct pathways.
Fenton, M. J., Vermeulen, M. W., Clark, B. D., Webb, A. C., & Auron, P. E. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.140.7.2267 · Cited by 201 · see citing works
CA074 methyl ester: A proinhibitor for intracellular cathepsin B
Buttle, D. J., Murata, M., Knight, C. G., & Barrett, A. J. (1992) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(92)90290-d · Cited by 201 · see citing works
Wang, X., Feuerstein, G., Gu, J.-L., Lysko, P. G., & Yue, T.-L. (1995) · Atherosclerosis · doi:10.1016/0021-9150(94)05503-b · Cited by 195 · see citing works
Schwartz, W. N., & Barrett, A. J. (1980) · Biochemical Journal · doi:10.1042/bj1910487 · Cited by 194 · see citing works
Crystallization of Free Cholesterol in Model Macrophage Foam Cells
Kellner-Weibel, G., Yancey, P. G., Jerome, W. G., Walser, T., Mason, R. P., Phillips, M. C., & Rothblat, G. H. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.8.1891 · Cited by 170 · see citing works
Montaser, M. M., Lalmanach, G., & Mach, L. (2002) · Biological Chemistry · doi:10.1515/bc.2002.147 · Cited by 167 · see citing works
Formation of cholesterol monohydrate crystals in macrophage-derived foam cells.
Tangirala, R. K., Jerome, W. G., Jones, N. L., SMALL, D. M., Johnson, W. J., Glick, J. M., Mahlberg, F. H., & Rothblat, G. H. (1994) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40131-2 · Cited by 147 · see citing works
Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness
Schoneveld, A. H., Hoefer, I. E., Sluijter, J. P. G., Laman, J. D., de Kleijn, D. P. V., & Pasterkamp, G. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.08.004 · Cited by 132 · see citing works
Galactose‐binding site in Escherichia coli heat‐labile enterotoxin (LT) and cholera toxin (CT)
Merritt, E. A., Sixma, T. K., Kalk, K. H., van Zanten, B. A. M., & Hol, W. G. J. (1994) · Molecular Microbiology · doi:10.1111/j.1365-2958.1994.tb00467.x · Cited by 129 · see citing works
Induction of nitric oxide synthase gene by interleukin in vascular smooth muscle cells.
Kanno, K., Hirata, Y., Tasuku, I. M. A. I., & Marumo, F. (1993) · Hypertension · doi:10.1161/01.hyp.22.1.34 · Cited by 123 · see citing works
Tm, B., Ta, S., & Guyton (1986) · PubMed · Cited by 111 · see citing works
Review: Transcriptional and post-transcriptional regulation of interleukin 1 gene expression
Fenton, M. J. (1992) · International Journal of Immunopharmacology · doi:10.1016/0192-0561(92)90170-p · Cited by 104 · see citing works
Guyton, J. R., & Klemp, K. F. (1993) · PubMed · Cited by 99 · see citing works
Dinarello, C. (1986) · PubMed · Cited by 95 · see citing works
Knight, C. G. (1980) · Biochemical Journal · doi:10.1042/bj1890447 · Cited by 90 · see citing works
Sequestration of acetylated LDL and cholesterol crystals by human monocyte-derived macrophages.
Kruth, H. S., Skarlatos, S. I., Lilly, K., Chang, J., & Ifrim, I. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.129.1.133 · Cited by 85 · see citing works
Cholesterol Solubility in Organic Solvents
Flynn, G. L., Shah, Y., Prakongpan, S., Kwan, K. H., Higuchi, W. I., & Hofmann, A. F. (1979) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600680908 · Cited by 80 · see citing works
Nakanishi, S., Vikstedt, R., Söderlund, S., Lee‐Rueckert, M., Hiukka, A., Ehnholm, C., Muilu, M., Metso, J., Naukkarinen, J., Palotie, L., et al. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800196-jlr200 · Cited by 60 · see citing works
Self-citationBoraschi, D., Villa, L., Volpini, G., Bossù, P., Censini, S., GHIARA, P., Scapigliat, G., Nencioni, L., Bartalini, M., Matteucci, G., et al. (1990) · European Journal of Immunology · doi:10.1002/eji.1830200213 · Cited by 58 · see citing works
Noorden, C. J. F. V., Boonacker, E., Bissell, E. R., Meijer, A. J., van Marle, J., & Smith, R. E. (1997) · Analytical Biochemistry · doi:10.1006/abio.1997.2312 · Cited by 48 · see citing works
The Roles of Pathogen-Associated Molecular Patterns in Atherosclerosis
Erridge, C. (2008) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2007.12.003 · Cited by 46 · see citing works
Interleukin-1β induces endothelin-1 gene by multiple mechanisms
Herman, W. H., Holcomb, J., Hricik, D. E., & Simonson, M. S. (1999) · Transplantation Proceedings · doi:10.1016/s0041-1345(98)02109-5 · Cited by 18 · see citing works
Huang, H., Park, C., Ryu, J., Chang, E., Lee, Y., Kang, S. S., & Kim, H. (2006) · Archives of Pharmacal Research · doi:10.1007/bf02973911 · Cited by 18 · see citing works
Cholesterol crystal uptake and metabolism by P388D1 macrophages
McConathy, W. J., Koren, E., & Stiers, D. L. (1989) · Atherosclerosis · doi:10.1016/0021-9150(89)90085-3 · Cited by 16 · see citing works
Kovács, T., Kárász, A., Szöllõsi, J., & Nagy, P. (2009) · Cytometry Part A · doi:10.1002/cyto.a.20756 · Cited by 14 · see citing works
Daws (2001) · doi:10.1002/1521-4141(200103)31:3
Self-citation
Flagged first, then by citations
2 of the 60 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
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 · see citing works
Progress and challenges in translating the biology of atherosclerosis
Libby, P., Ridker, P. M., & Hansson, G. K. (2011) · Nature · doi:10.1038/nature10146 · Cited by 4,010 · see citing works
Macrophages in the Pathogenesis of Atherosclerosis
Moore, K. J., & Tabas, I. (2011) · Cell · doi:10.1016/j.cell.2011.04.005 · Cited by 2,669 · see citing works
The immune system in atherosclerosis
Hansson, G. K., & Hermansson, A. (2011) · Nature Immunology · doi:10.1038/ni.2001 · Cited by 2,331 · see citing works
Atherosclerosis: current pathogenesis and therapeutic options
Weber, C., & Noels, H. (2011) · Nature Medicine · doi:10.1038/nm.2538 · Cited by 2,203 · see citing works
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 · see citing works
Self-citationAge and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267 · see citing works
NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice
Mridha, A. R., Wree, A., Robertson, A. A. B., Yeh, M. M., Johnson, C. D., Van Rooyen, D. M., Haczeyni, F., Teoh, N. C.-H., Savard, C., Ioannou, G. N., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.01.022 · Cited by 1,110 · see citing works
Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure
Świrski, F. K., & Nahrendorf, M. (2013) · Science · doi:10.1126/science.1230719 · Cited by 1,088 · see citing works
Ridker, P. M. (2016) · Circulation Research · doi:10.1161/circresaha.115.306656 · Cited by 1,002 · see citing works
The immunology of atherosclerosis
Gisterå, A., & Hansson, G. K. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.51 · Cited by 982 · see citing works
Ginsberg, H. N., Packard, C. J., Chapman, M. J., Borén, J., Aguilar-Salinas, C. A., Averna, M., Ference, B. A., Gaudet, D., Hegele, R. A., Kersten, S., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab551 · Cited by 979 · see citing works
Triggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943 · see citing works
Sheedy, F. J., Grebe, A., Rayner, K. J., Kalantari, P., Ramkhelawon, B., Carpenter, S. B., Becker, C. E., Ediriweera, H. N., Mullick, A. E., Golenbock, D. T., et al. (2013) · Nature Immunology · doi:10.1038/ni.2639 · Cited by 935 · see citing works
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 · see citing works
Western Diet and the Immune System: An Inflammatory Connection
Christ, A., Lauterbach, M., & Latz, E. (2019) · Immunity · doi:10.1016/j.immuni.2019.09.020 · Cited by 907 · see citing works
Ridker, P. M., Thuren, T., Zalewski, A., & Libby, P. (2011) · American Heart Journal · doi:10.1016/j.ahj.2011.06.012 · Cited by 799 · see citing works
Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease
Abbate, A., Toldo, S. A., Marchetti, C., Kron, J., Tassell, B. W. V., & Dinarello, C. A. (2020) · Circulation Research · doi:10.1161/circresaha.120.315937 · Cited by 744 · see citing works
Abderrazak, A., Syrovets, T., Couchie, D., Hadri, K. E., Friguet, B., Simmet, T., & Rouis, M. (2015) · Redox Biology · doi:10.1016/j.redox.2015.01.008 · Cited by 737 · see citing works
Liver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722 · see citing works
Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans
Libby, P., Lichtman, A. H., & Hansson, G. K. (2013) · Immunity · doi:10.1016/j.immuni.2013.06.009 · Cited by 667 · see citing works
Interleukin-1 Beta as a Target for Atherosclerosis Therapy
Libby, P. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.09.028 · Cited by 629 · see citing works
Autophagy Links Inflammasomes to Atherosclerotic Progression
Razani, B., Feng, C., Coleman, T., Emanuel, R., Wen, H., Hwang, S., Ting, J. P., Virgin, H. W., Kastan, M. B., & Semenkovich, C. F. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.02.011 · Cited by 601 · see citing works
Chen, M., Zhu, X., Ran, L., Lang, H., Yi, L., & Mi, M. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006347 · Cited by 600 · see citing works
Defective cholesterol clearance limits remyelination in the aged central nervous system
Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.-T., Su, M., Sen, P., Ruhwedel, T., Mitkovski, M., Trendelenburg, G., Lütjohann, D., et al. (2018) · Science · doi:10.1126/science.aan4183 · Cited by 586 · see citing works
Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies
Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L., & de Bernard, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055375 · Cited by 585 · see citing works
Recent insights into the pathogenesis of nonalcoholic fatty liver disease
Arab, J. P., Arrese, M., & Trauner, M. (2018) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020117-043617 · Cited by 573 · see citing works
Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target
Golia, E., Limongelli, G., Natale, F., Fimiani, F., Maddaloni, V., Pariggiano, I., Bianchi, R., Crisci, M., D’Acierno, L., Giordano, R. C., et al. (2014) · Current Atherosclerosis Reports · doi:10.1007/s11883-014-0435-z · Cited by 564 · see citing works
Anti-inflammatory therapies for cardiovascular disease
Ridker, P. M., & Lüscher, T. F. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu203 · Cited by 558 · see citing works
Duan, Y., Gong, K., Xu, S., Zhang, F., Meng, X., & Han, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01125-5 · Cited by 538 · see citing works
Inflammaging: disturbed interplay between autophagy and inflammasomes
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2012) · Aging · doi:10.18632/aging.100444 · Cited by 511 · see citing works
The Role of Cholesterol in the Pathogenesis of NASH
Ioannou, G. N. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.11.008 · Cited by 498 · see citing works
Reactive oxygen species at the crossroads of inflammasome and inflammation
Harijith, A. K., Ebenezer, D. L., & Natarajan, V. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00352 · Cited by 474 · see citing works
Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion
Mulay, S. R., Kulkarni, O. P., Rupanagudi, K. V., Migliorini, A., Darisipudi, M. N., Vilaysane, A., Muruve, D. A., Shi, Y., Munro, F., Liapis, H., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63679 · Cited by 474 · see citing works
Molecular Biology of Atherosclerosis
Hopkins, P. N. (2013) · Physiological Reviews · doi:10.1152/physrev.00004.2012 · Cited by 456 · see citing works
A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation?
Wen, H., Ting, J. P. ‐., & O'Neill, L. A. J. (2012) · Nature Immunology · doi:10.1038/ni.2228 · Cited by 455 · see citing works
NLRP3 inflammasome: Its regulation and involvement in atherosclerosis
Hoseini, Z. S., Sepahvand, F., Rashidi, B., Sahebkar, A., Masoudifar, A., & Mirzaei, H. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25930 · Cited by 458 · see citing works
Uric acid as a danger signal in gout and its comorbidities
Rock, K. L., Kataoka, H., & Lai, J. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.143 · Cited by 453 · see citing works
The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease
Wang, S., Yuan, Y., Chen, N., & Wang, H. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.12.019 · Cited by 447 · see citing works
Role of innate and adaptive immunity in obesity-associated metabolic disease
McLaughlin, T., Ackerman, S. E., Shen, L., & Engleman, E. G. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88876 · Cited by 444 · see citing works
The NLRP3 inflammasome: Mechanism of action, role in disease and therapies
Wang, L., & Hauenstein, A. V. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100889 · Cited by 426 · see citing works
The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases
Toldo, S. A., & Abbate, A. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00946-3 · Cited by 437 · see citing works
NLRP3 inflammasomes link inflammation and metabolic disease
De Nardo, D., & Latz, E. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.05.004 · Cited by 425 · see citing works
Uric acid, hyperuricemia and vascular diseases
Jin, M. J. (2011) · Frontiers in bioscience · doi:10.2741/3950 · Cited by 416 · see citing works
Colchicine in Patients With Acute Coronary Syndrome
Tong, D. C., Quinn, S. J., Nasis, A., Hiew, C., Roberts‐Thomson, P., Adams, H. S. L., Sriamareswaran, R. K., Htun, N., WILSON, W. M., Stub, D. A., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.050771 · Cited by 407 · see citing works
Angiogenesis in the atherosclerotic plaque
Camaré, C., Pucelle, M., Nègre-Salvayre, A., & Salvayre, R. (2017) · Redox Biology · doi:10.1016/j.redox.2017.01.007 · Cited by 401 · see citing works
Koushki, K., Shahbaz, S. K., Mashayekhi, K., Sadeghi, M., Zayeri, Z. D., Taba, M. Y., Banach, M., Al-Rasadi, K., Johnston, T. P., & Sahebkar, A. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-020-08791-9 · Cited by 382 · see citing works
Anti-inflammatory therapies for atherosclerosis
Bäck, M., & Hansson, G. K. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.5 · Cited by 380 · see citing works
InflammasomesPreprint
de Zoete, M. R., Palm, N. W., Zhu, S., & Flavell, R. A. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016287 · Cited by 382 · see citing works
Intraplaque haemorrhages as the trigger of plaque vulnerability
Michel, J., Virmani, R., Arbustini, E., & Pasterkamp, G. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr054 · Cited by 379 · see citing works
Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome
Rajamäki, K., Nordström, T., Nurmi, K., Åkerman, K. E. O., Kovanen, P. T., Öörni, K., & Eklund, K. K. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.426254 · Cited by 355 · see citing works
Self-citationMacrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis
Bobryshev, Y. V., Ivanova, E. A., Chistiakov, D. A., Nikiforov, N. G., & Orekhov, A. N. (2016) · BioMed Research International · doi:10.1155/2016/9582430 · Cited by 354 · see citing works
Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis
Sergin, I., Evans, T. D., Zhang, X., Bhattacharya, S., Stokes, C. J., Song, E., Ali, S., Dehestani, B., Holloway, K. B., Micevych, P. S., et al. (2017) · Nature Communications · doi:10.1038/ncomms15750 · Cited by 351 · see citing works
van der Heijden, T., Kritikou, E., Venema, W., van Duijn, J., van Santbrink, P. J., Slütter, B., Foks, A. C., Bot, I., & Kuiper, J. (2017) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.309575 · Cited by 348 · see citing works
Martínez, G. J., Celermajer, D. S., & Patel, S. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.12.027 · Cited by 346 · see citing works
Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity
Donath, M. Y., Dalmas, É., Sauter, N. S., & Böni-Schnetzler, M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.001 · Cited by 338 · see citing works
Pathogenesis of acute stroke and the role of inflammasomes
Fann, D. Y., Lee, S.-Y., Manzanero, S., Chunduri, P., Sobey, C. G., & Arumugam, T. V. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.09.004 · Cited by 334 · see citing works
Pyroptosis and its relationship to atherosclerosis
Xu, Y., Zheng, L., Hu, Y., & Wang, Q. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.11.005 · Cited by 322 · see citing works
Exosome-like Nanoparticles from Ginger Rhizomes Inhibited NLRP3 Inflammasome Activation
Chen, X., Zhou, Y., & Yu, J. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.9b00246 · Cited by 320 · see citing works
Freigang, S., Ampenberger, F., Weiss, A., Kanneganti, T., Iwakura, Y., Hersberger, M., & Köpf, M. (2013) · Nature Immunology · doi:10.1038/ni.2704 · Cited by 304 · see citing works
NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
Paramel, G. V., Folkersen, L., Strawbridge, R. J., Halvorsen, B. L., Yndestad, A., Ranheim, T., Krohg‐Sørensen, K., Skjelland, M., Espevik, T., Aukrust, P., et al. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.003031 · Cited by 308 · see citing works
Recent insights on the role of cholesterol in non-alcoholic fatty liver disease
Argüello, G., Balboa, E., Arrese, M. A., & Zanlungo, S. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.05.015 · Cited by 306 · see citing works
The Thioredoxin System as a Therapeutic Target in Human Health and Disease
Mahmood, D. F. D., Abderrazak, A., Hadri, K. E., Simmet, T., & Rouis, M. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4757 · Cited by 305 · see citing works
Crosstalk between ER stress, NLRP3 inflammasome, and inflammation
Li, W., Cao, T., Luo, C., Cai, J., Zhou, X., Xiao, X., & Liu, S.-Q. (2020) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-020-10614-y · Cited by 278 · see citing works
Salminen, A., Ojala, J. O., Kaarniranta, K., & Kauppinen, A. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0962-0 · Cited by 304 · see citing works
Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000484623 · Cited by 302 · see citing works
Targeting Interleukin-1 in Heart Disease
Tassell, B. W. V., Toldo, S. A., Mezzaroma, E., & Abbate, A. (2013) · Circulation · doi:10.1161/circulationaha.113.003199 · Cited by 306 · see citing works
Freigang, S., Ampenberger, F., Spohn, G., Heer, S., Shamshiev, A. T., Kisielow, J., Hersberger, M., Yamamoto, M., Bachmann, M. F., & Kopf, M. (2011) · European Journal of Immunology · doi:10.1002/eji.201041316 · Cited by 300 · see citing works
Niemi, K., Teirilä, L., Lappalainen, J., Rajamäki, K., Baumann, M. H., Öörni, K., Wolff, H., Kovanen, P. T., Matikainen, S., & Eklund, K. K. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002843 · Cited by 298 · see citing works
Self-citationPerera, A. P., Fernando, R., Shinde, T., Gundamaraju, R., Southam, B., Sohal, S. S., Robertson, A. A. B., Schroder, K., Kunde, D., & Eri, R. D. (2018) · Scientific Reports · doi:10.1038/s41598-018-26775-w · Cited by 300 · see citing works
Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis
Giordano, A., Murano, I., Mondini, E., Perugini, J., Smorlesi, A., Severi, I., Barazzoni, R., Scherer, P. E., & Cinti, S. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m038638 · Cited by 297 · see citing works
Inflammasomes on the Crossroads of Innate Immune Recognition and Metabolic Control
Próchnicki, T., & Latz, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.018 · Cited by 297 · see citing works
The Inflammasomes and Autoinflammatory Syndromes
Broderick, L., Nardo, D. D., Franklin, B. S., Hoffman, H. M., & Latz, E. (2014) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040431 · Cited by 296 · see citing works
Metabolic Modulation in Macrophage Effector Function
Diskin, C., & Pålsson‐McDermott, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00270 · Cited by 292 · see citing works
van Diepen, J. A., Berbée, J. F. P., Havekes, L. M., & Rensen, P. C. N. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.02.028 · Cited by 292 · see citing works
Tseng, W. A., Thein, T., Kinnunen, K., Lashkari, K., Gregory, M. S., D'Amore, P. A., & Ksander, B. R. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-10655 · Cited by 287 · see citing works
Cholesterol Crystals Induce Complement-Dependent Inflammasome Activation and Cytokine Release
Samstad, E. O., Niyonzima, N., Nymo, S. H., Aune, M. H., Ryan, L., Bakke, S. S., Lappegård, K. T., Brekke, O., Lambris, J. D., Damås, J. K., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302484 · Cited by 286 · see citing works
Martínez, G. J., Robertson, S. E. J., Barraclough, J., Xia, Q., Mallat, Z., Bursill, C. A., Celermajer, D. S., & Patel, S. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002128 · Cited by 285 · see citing works
DAMPs as mediators of sterile inflammation in aging-related pathologies
Feldman, N., Rotter-Maskowitz, A., & Okun, E. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.003 · Cited by 283 · see citing works
Sensing damage by the NLRP3 inflammasome
Leemans, J. C., Cassel, S. L., & Sutterwala, F. S. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01043.x · Cited by 281 · see citing works
The Influence of Innate and Adaptive Immune Responses on Atherosclerosis
Witztum, J. L., & Lichtman, A. H. (2013) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163936 · Cited by 277 · see citing works
Role of NLRP3 Inflammasomes in Atherosclerosis
Karasawa, T., & Takahashi, M. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17001 · Cited by 277 · see citing works
Dobrev, D., Heijman, J., Hiram, R., Li, N., & Nattel, S. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00759-w · Cited by 272 · see citing works
Multiple cathepsins promote pro-IL-1β synthesis and NLRP3-mediated IL-1β activation
Orlowski, G. M., Colbert, J. D., Sharma, S., Bogyo, M., Robertson, S. A., & Rock, K. L. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500509 · Cited by 268 · see citing works
Mechanisms That Regulate Macrophage Burden in Atherosclerosis
Randolph, G. J. (2014) · Circulation Research · doi:10.1161/circresaha.114.301174 · Cited by 265 · see citing works
Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases
Liu, D., Zeng, X., Xiao, L., Mehta, J. L., & Wang, X. (2017) · Basic Research in Cardiology · doi:10.1007/s00395-017-0663-9 · Cited by 260 · see citing works
Xiao, H., Lu, M., Lin, T. Y., Chen, Z., Chen, G., Wang, W.-C., Marin, T., Shentu, T.-P., Wen, L., Gongol, B., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.002714 · Cited by 257 · see citing works
Phenotypic Polarization of Macrophages in Atherosclerosis
Leitinger, N., & Schulman, I. G. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.300173 · Cited by 257 · see citing works
Ma, Q. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000629 · Cited by 256 · see citing works
Pathogenesis of Acute Coronary Syndromes
Crea, F., & Liuzzo, G. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.07.064 · Cited by 247 · see citing works
Segovia, J. A., Sabbah, A., Mgbemena, V. E., Tsai, S.-Y., Chang, T.-H., Berton, M. T., Morris, I. R., Allen, I. C., Ting, J. P. ‐., & Bose, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029695 · Cited by 247 · see citing works
Øvrevik, J., Refsnes, M., Låg, M., Holme, J. A., & Schwarze, P. E. (2015) · Biomolecules · doi:10.3390/biom5031399 · Cited by 240 · see citing works
Wang, C., Pan, Y., Zhang, Q.-Y., Wang, F., & Kong, L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038285 · Cited by 233 · see citing works
Emanuel, R., Sergin, I., Bhattacharya, S., Turner, J. N., Epelman, S., Settembre, C., Diwan, A., Ballabio, A., & Razani, B. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.303342 · Cited by 228 · see citing works
Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis
Li, H., Yu, X.-H., Ou, X., Ouyang, X.-P., & Tang, C. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101109 · Cited by 230 · see citing works
Liu, W., Yin, Y., Zhou, Z., He, M. Y., & Dai, Y. (2013) · Inflammation Research · doi:10.1007/s00011-013-0667-3 · Cited by 223 · see citing works
Crittenden, D. B., Lehmann, R. A., SCHNECK, L., Keenan, R. T., Shah, B., Greenberg, J. D., Cronstein, B. N., Sedlis, S. P., & Pillinger, M. H. (2012) · The Journal of Rheumatology · doi:10.3899/jrheum.111533 · Cited by 223 · see citing works
Inflammation and Stroke Risk: A New Target for Prevention
Kelly, P. J., Lemmens, R., & Tsivgoulis, G. K. (2021) · Stroke · doi:10.1161/strokeaha.121.034388 · Cited by 218 · see citing works
The role of the NLRP3 inflammasome in gout
McDermott, M., Kingsbury, S. R., & Conaghan, P. G. (2011) · Journal of Inflammation Research · doi:10.2147/jir.s11330 · Cited by 221 · see citing works
From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk
Shapiro, M. D., & Fazio, S. (2016) · Circulation Research · doi:10.1161/circresaha.115.306471 · Cited by 217 · see citing works
- 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
- Health Sciences › Medicine › Surgery › 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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