The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of dea...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.642855/full |
| _version_ | 1818931491845963776 |
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| author | Benedikt Jäger Benedikt Jäger Benedikt Jäger Benjamin Seeliger Oliver Terwolbeck Gregor Warnecke Tobias Welte Meike Müller Christian Bode Antje Prasse Antje Prasse Antje Prasse |
| author_facet | Benedikt Jäger Benedikt Jäger Benedikt Jäger Benjamin Seeliger Oliver Terwolbeck Gregor Warnecke Tobias Welte Meike Müller Christian Bode Antje Prasse Antje Prasse Antje Prasse |
| author_sort | Benedikt Jäger |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro. We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF. |
| first_indexed | 2024-12-20T04:17:27Z |
| format | Article |
| id | doaj.art-4ed61995440d48c6a4c13b405fb5200e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T04:17:27Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4ed61995440d48c6a4c13b405fb5200e2022-12-21T19:53:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-04-011210.3389/fimmu.2021.642855642855The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 CellsBenedikt Jäger0Benedikt Jäger1Benedikt Jäger2Benjamin Seeliger3Oliver Terwolbeck4Gregor Warnecke5Tobias Welte6Meike Müller7Christian Bode8Antje Prasse9Antje Prasse10Antje Prasse11Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, GermanyDepartment of Respiratory Medicine, University Medical Center, Freiburg, GermanyFaculty of Biology, Albert Ludwig University, Freiburg, GermanyDepartment of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, GermanyFraunhofer Institute for Toxicology and Experimental Medicine, Hannover, GermanyDepartment of Heart, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, GermanyDepartment of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, GermanyFraunhofer Institute for Toxicology and Experimental Medicine, Hannover, GermanyDepartment of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, GermanyFraunhofer Institute for Toxicology and Experimental Medicine, Hannover, GermanyDepartment of Respiratory Medicine, University Medical Center, Freiburg, GermanyDepartment of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, GermanyIdiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro. We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF.https://www.frontiersin.org/articles/10.3389/fimmu.2021.642855/fullidiopathic pulmonary fibrosisinflammasomeNLRP3acute exacerbationinflammation |
| spellingShingle | Benedikt Jäger Benedikt Jäger Benedikt Jäger Benjamin Seeliger Oliver Terwolbeck Gregor Warnecke Tobias Welte Meike Müller Christian Bode Antje Prasse Antje Prasse Antje Prasse The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells Frontiers in Immunology idiopathic pulmonary fibrosis inflammasome NLRP3 acute exacerbation inflammation |
| title | The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells |
| title_full | The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells |
| title_fullStr | The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells |
| title_full_unstemmed | The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells |
| title_short | The NLRP3-Inflammasome-Caspase-1 Pathway Is Upregulated in Idiopathic Pulmonary Fibrosis and Acute Exacerbations and Is Inducible by Apoptotic A549 Cells |
| title_sort | nlrp3 inflammasome caspase 1 pathway is upregulated in idiopathic pulmonary fibrosis and acute exacerbations and is inducible by apoptotic a549 cells |
| topic | idiopathic pulmonary fibrosis inflammasome NLRP3 acute exacerbation inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.642855/full |
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