ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and elec...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/49248 |
| _version_ | 1811181536361316352 |
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| author | Thomas Scambler Heledd H Jarosz-Griffiths Samuel Lara-Reyna Shelly Pathak Chi Wong Jonathan Holbrook Fabio Martinon Sinisa Savic Daniel Peckham Michael F McDermott |
| author_facet | Thomas Scambler Heledd H Jarosz-Griffiths Samuel Lara-Reyna Shelly Pathak Chi Wong Jonathan Holbrook Fabio Martinon Sinisa Savic Daniel Peckham Michael F McDermott |
| author_sort | Thomas Scambler |
| collection | DOAJ |
| description | Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation. |
| first_indexed | 2024-04-11T09:19:03Z |
| format | Article |
| id | doaj.art-4da6ca1aca8646a0aba1a7636105b237 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:19:03Z |
| publishDate | 2019-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4da6ca1aca8646a0aba1a7636105b2372022-12-22T04:32:15ZengeLife Sciences Publications LtdeLife2050-084X2019-09-01810.7554/eLife.49248ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosisThomas Scambler0https://orcid.org/0000-0003-2468-0218Heledd H Jarosz-Griffiths1https://orcid.org/0000-0001-5154-4815Samuel Lara-Reyna2https://orcid.org/0000-0002-9986-5279Shelly Pathak3Chi Wong4https://orcid.org/0000-0003-2108-1615Jonathan Holbrook5Fabio Martinon6https://orcid.org/0000-0002-6969-822XSinisa Savic7https://orcid.org/0000-0001-7910-0554Daniel Peckham8https://orcid.org/0000-0001-7723-1868Michael F McDermott9https://orcid.org/0000-0002-1015-0745Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Institute of Medical Research, University of Leeds, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United KingdomLeeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom; Department of Biochemistry, University of Lausanne, Lausanne, SwitzerlandLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom; Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, United KingdomLeeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom; Adult Cystic Fibrosis Unit, St James’ University Hospital, Leeds, United KingdomLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom; Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United KingdomCystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.https://elifesciences.org/articles/49248inflammasomecystic fibrosissodium transportpotassium transportautoinflammationNLRP3 |
| spellingShingle | Thomas Scambler Heledd H Jarosz-Griffiths Samuel Lara-Reyna Shelly Pathak Chi Wong Jonathan Holbrook Fabio Martinon Sinisa Savic Daniel Peckham Michael F McDermott ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis eLife inflammasome cystic fibrosis sodium transport potassium transport autoinflammation NLRP3 |
| title | ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis |
| title_full | ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis |
| title_fullStr | ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis |
| title_full_unstemmed | ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis |
| title_short | ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis |
| title_sort | enac mediated sodium influx exacerbates nlrp3 dependent inflammation in cystic fibrosis |
| topic | inflammasome cystic fibrosis sodium transport potassium transport autoinflammation NLRP3 |
| url | https://elifesciences.org/articles/49248 |
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