ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis
| Autor: | Daniel Peckham, Fabio Martinon, C. Wong, Heledd H. Jarosz-Griffiths, Shelly Pathak, Samuel Lara-Reyna, Sinisa Savic, T. Scambler, Michael F. McDermott, J. Holbrook |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Epithelial sodium channel Cystic fibrosis potassium transport cystic fibrosis Immunology and Inflammation 0302 clinical medicine Biology (General) biology Chemistry General Neuroscience sodium transport Inflammasome General Medicine respiratory system autoinflammation Cystic fibrosis transmembrane conductance regulator 3. Good health 030220 oncology & carcinogenesis Medicine medicine.symptom Research Article Human medicine.drug medicine.medical_specialty QH301-705.5 Science Inflammation General Biochemistry Genetics and Molecular Biology Cell Line Proinflammatory cytokine 03 medical and health sciences NLRP3 Downregulation and upregulation inflammasome Internal medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Humans Epithelial Sodium Channels Human Biology and Medicine General Immunology and Microbiology Sodium Bicarbonate transport medicine.disease Immunity Innate 030104 developmental biology Endocrinology Cystic Fibrosis/pathology Epithelial Sodium Channels/metabolism Inflammation/pathology NLR Family Pyrin Domain-Containing 3 Protein/metabolism Sodium/metabolism human human biology immunology inflammation biology.protein |
| Zdroj: | eLife, vol. 8 eLife, Vol 8 (2019) eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.49248 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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