Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines
Tissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1&#...
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MDPI AG
2019-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/1/79 |
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| author | Nilay Köse-Vogel Sven Stengel Elena Gardey Tatiana Kirchberger-Tolstik Philipp A. Reuken Andreas Stallmach Tony Bruns |
| author_facet | Nilay Köse-Vogel Sven Stengel Elena Gardey Tatiana Kirchberger-Tolstik Philipp A. Reuken Andreas Stallmach Tony Bruns |
| author_sort | Nilay Köse-Vogel |
| collection | DOAJ |
| description | Tissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1β have been identified as important mediators of fibrosis. Epirubicin, an anthracycline topoisomerase II inhibitor, has been reported to inhibit myeloid inflammatory cytokine production and to promote tissue tolerance following bacterial infection. We investigated the anti-inflammatory properties of epirubicin on the NLRP3 inflammasome and TLR4-mediated inflammation in PMA-primed THP-1 and in primary human peritoneal macrophages (PM). Low-dose epirubicin at non-cytotoxic doses downregulated NLRP3 inflammasome components and reduced the release of cleaved caspase-1, bioactive IL-1β, and TNF-α following NLRP3 activation in a dose-dependent fashion. In addition, epirubicin attenuated inflammatory macrophage responses after TLR4 and TLR2 ligation. These anti-inflammatory effects were not mediated by the induction of autophagy or altered MAPK signaling, but as the result of a global transcriptional suppression of LPS-dependent genes. Epirubicin-treated macrophages displayed reduced acetylation of histone 3 lysine 9 (H3K9ac), suggesting anti-inflammatory epigenetic imprinting as one underlying mechanism. |
| first_indexed | 2024-03-12T04:41:51Z |
| format | Article |
| id | doaj.art-51b370e6c1c14a6680c3a30f263f5470 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T04:41:51Z |
| publishDate | 2019-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-51b370e6c1c14a6680c3a30f263f54702023-09-03T09:37:05ZengMDPI AGCells2073-44092019-12-01917910.3390/cells9010079cells9010079Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose AnthracyclinesNilay Köse-Vogel0Sven Stengel1Elena Gardey2Tatiana Kirchberger-Tolstik3Philipp A. Reuken4Andreas Stallmach5Tony Bruns6Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyDepartment of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, GermanyTissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1β have been identified as important mediators of fibrosis. Epirubicin, an anthracycline topoisomerase II inhibitor, has been reported to inhibit myeloid inflammatory cytokine production and to promote tissue tolerance following bacterial infection. We investigated the anti-inflammatory properties of epirubicin on the NLRP3 inflammasome and TLR4-mediated inflammation in PMA-primed THP-1 and in primary human peritoneal macrophages (PM). Low-dose epirubicin at non-cytotoxic doses downregulated NLRP3 inflammasome components and reduced the release of cleaved caspase-1, bioactive IL-1β, and TNF-α following NLRP3 activation in a dose-dependent fashion. In addition, epirubicin attenuated inflammatory macrophage responses after TLR4 and TLR2 ligation. These anti-inflammatory effects were not mediated by the induction of autophagy or altered MAPK signaling, but as the result of a global transcriptional suppression of LPS-dependent genes. Epirubicin-treated macrophages displayed reduced acetylation of histone 3 lysine 9 (H3K9ac), suggesting anti-inflammatory epigenetic imprinting as one underlying mechanism.https://www.mdpi.com/2073-4409/9/1/79inflammationmacrophagesinnate immunityinnate immune memoryhistonesepigenetics |
| spellingShingle | Nilay Köse-Vogel Sven Stengel Elena Gardey Tatiana Kirchberger-Tolstik Philipp A. Reuken Andreas Stallmach Tony Bruns Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines Cells inflammation macrophages innate immunity innate immune memory histones epigenetics |
| title | Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines |
| title_full | Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines |
| title_fullStr | Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines |
| title_full_unstemmed | Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines |
| title_short | Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines |
| title_sort | transcriptional suppression of the nlrp3 inflammasome and cytokine release in primary macrophages by low dose anthracyclines |
| topic | inflammation macrophages innate immunity innate immune memory histones epigenetics |
| url | https://www.mdpi.com/2073-4409/9/1/79 |
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