Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects
Abstract Inflammation driven by intracellular activation of the NLRP3 inflammasome is involved in the pathogenesis of a variety of diseases including vascular pathologies. Inflammasome specks are released into the extracellular compartment from disrupting pyroptotic cells. The potential uptake and f...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-94314-1 |
| _version_ | 1818347124867203072 |
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| author | Susanne Gaul Karen Marie Schaeffer Lena Opitz Christina Maeder Alexander Kogel Luisa Uhlmann Hermann Kalwa Ulf Wagner Jan Haas Amirhossein Behzadi Pablo Pelegrin Jes-Niels Boeckel Ulrich Laufs |
| author_facet | Susanne Gaul Karen Marie Schaeffer Lena Opitz Christina Maeder Alexander Kogel Luisa Uhlmann Hermann Kalwa Ulf Wagner Jan Haas Amirhossein Behzadi Pablo Pelegrin Jes-Niels Boeckel Ulrich Laufs |
| author_sort | Susanne Gaul |
| collection | DOAJ |
| description | Abstract Inflammation driven by intracellular activation of the NLRP3 inflammasome is involved in the pathogenesis of a variety of diseases including vascular pathologies. Inflammasome specks are released into the extracellular compartment from disrupting pyroptotic cells. The potential uptake and function of extracellular NLRP3 inflammasomes in human coronary artery smooth muscle cells (HCASMC) are unknown. Fluorescently labeled NLRP3 inflammasome particles were isolated from a mutant NLRP3-YFP cell line and used to treat primary HCASMC for 4 and 24 h. Fluorescent and expressional analyses showed that extracellular NLRP3-YFP particles are internalized into HCASMC, where they remain active and stimulate intracellular caspase-1 (1.9-fold) and IL-1β (1.5-fold) activation without inducing pyroptotic cell death. Transcriptomic analysis revealed increased expression level of pro-inflammatory adhesion molecules (ICAM1, CADM1), NLRP3 and genes involved in cytoskleleton organization. The NLRP3-YFP particle-induced gene expression was not dependent on NLRP3 and caspase-1 activation. Instead, the effects were partly abrogated by blocking NFκB activation. Genes, upregulated by extracellular NLRP3 were validated in human carotid artery atheromatous plaques. Extracellular NLRP3-YFP inflammasome particles promoted the secretion of pro-atherogenic and inflammatory cytokines such as CCL2/MCP1, CXCL1 and IL-17E, and increased HCASMC migration (1.8-fold) and extracellular matrix production, such as fibronectin (5.8-fold) which was dependent on NFκB and NLRP3 activation. Extracellular NLRP3 inflammasome particles are internalized into human coronary artery smooth muscle cells where they induce pro-inflammatory and pro-atherogenic effects representing a novel mechanism of cell-cell communication and perpetuation of inflammation in atherosclerosis. Therefore, extracellular NLRP3 inflammasomes may be useful to improve the diagnosis of inflammatory diseases and the development of novel anti-inflammatory therapeutic strategies. |
| first_indexed | 2024-12-13T17:29:11Z |
| format | Article |
| id | doaj.art-b6bb569c414c44e89dd851a34202c360 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T17:29:11Z |
| publishDate | 2021-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-b6bb569c414c44e89dd851a34202c3602022-12-21T23:37:06ZengNature PortfolioScientific Reports2045-23222021-07-0111111310.1038/s41598-021-94314-1Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effectsSusanne Gaul0Karen Marie Schaeffer1Lena Opitz2Christina Maeder3Alexander Kogel4Luisa Uhlmann5Hermann Kalwa6Ulf Wagner7Jan Haas8Amirhossein Behzadi9Pablo Pelegrin10Jes-Niels Boeckel11Ulrich Laufs12Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityMedical Faculty, Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Leipzig UniversityKlinik für Gastroenterologie, Hepatologie, Infektionsmedizin, Rheumatologie, Universitätsklinikum LeipzigDepartment of Internal Medicine III, University of HeidelbergKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityBiomedical Research Institute of Murcia (IMIB-Arrixaca), Clinical University Hospital Virgen de La ArrixacaKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityKlinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig UniversityAbstract Inflammation driven by intracellular activation of the NLRP3 inflammasome is involved in the pathogenesis of a variety of diseases including vascular pathologies. Inflammasome specks are released into the extracellular compartment from disrupting pyroptotic cells. The potential uptake and function of extracellular NLRP3 inflammasomes in human coronary artery smooth muscle cells (HCASMC) are unknown. Fluorescently labeled NLRP3 inflammasome particles were isolated from a mutant NLRP3-YFP cell line and used to treat primary HCASMC for 4 and 24 h. Fluorescent and expressional analyses showed that extracellular NLRP3-YFP particles are internalized into HCASMC, where they remain active and stimulate intracellular caspase-1 (1.9-fold) and IL-1β (1.5-fold) activation without inducing pyroptotic cell death. Transcriptomic analysis revealed increased expression level of pro-inflammatory adhesion molecules (ICAM1, CADM1), NLRP3 and genes involved in cytoskleleton organization. The NLRP3-YFP particle-induced gene expression was not dependent on NLRP3 and caspase-1 activation. Instead, the effects were partly abrogated by blocking NFκB activation. Genes, upregulated by extracellular NLRP3 were validated in human carotid artery atheromatous plaques. Extracellular NLRP3-YFP inflammasome particles promoted the secretion of pro-atherogenic and inflammatory cytokines such as CCL2/MCP1, CXCL1 and IL-17E, and increased HCASMC migration (1.8-fold) and extracellular matrix production, such as fibronectin (5.8-fold) which was dependent on NFκB and NLRP3 activation. Extracellular NLRP3 inflammasome particles are internalized into human coronary artery smooth muscle cells where they induce pro-inflammatory and pro-atherogenic effects representing a novel mechanism of cell-cell communication and perpetuation of inflammation in atherosclerosis. Therefore, extracellular NLRP3 inflammasomes may be useful to improve the diagnosis of inflammatory diseases and the development of novel anti-inflammatory therapeutic strategies.https://doi.org/10.1038/s41598-021-94314-1 |
| spellingShingle | Susanne Gaul Karen Marie Schaeffer Lena Opitz Christina Maeder Alexander Kogel Luisa Uhlmann Hermann Kalwa Ulf Wagner Jan Haas Amirhossein Behzadi Pablo Pelegrin Jes-Niels Boeckel Ulrich Laufs Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects Scientific Reports |
| title | Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects |
| title_full | Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects |
| title_fullStr | Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects |
| title_full_unstemmed | Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects |
| title_short | Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects |
| title_sort | extracellular nlrp3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro atherogenic effects |
| url | https://doi.org/10.1038/s41598-021-94314-1 |
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