Scambler, T, Jarosz-Griffiths, HH orcid.org/0000-0001-5154-4815, Lara-Reyna, S et al. (7 more authors) (2019) Excessive ENaC-mediated sodium influx drives NLRP3 inflammasome-dependent autoinflammation in cystic fibrosis. eLife, 8. e49248. ISSN 2050-084X
Abstract
Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and results in defective CFTR-mediated chloride transport, dysregulation of epithelial sodium channels (ENaC) and exaggerated innate immune responses. We tested the hypothesis that upregulation of ENaC drives autoinflammation in this complex monogenic disease.</jats:p><jats:p>We show that monocytes from patients with CF exhibit a systemic proinflammatory cytokine signature, with associated anti-inflammatory M2-type macrophage deficiency. Cells harboring CF mutations are hyperresponsive to NLRP3 stimulation, as evidenced by increased IL-18, IL-1β, ASC-specks levels in serum and caspase-1 activity in monocytes, and by increased IL-18 production and caspase-1 activity in human bronchial epithelial cells (HBECs). In both cell types there is an associated shift to glycolytic metabolism with succinate release, in response to increased energy requirements. Inhibition of amiloride-sensitive sodium channels partially reverses the NLRP3-dependent inflammation and metabolic shift in these cells. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increases NLRP3-dependent inflammation, indicating a CFTR-independent ENaC axis in CF pathophysiology. Sodium channel modulation provides an important therapeutic strategy to combat lung inflammation in CF.</jats:p>
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright Scambler et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Clinical Musculoskeletal Medicine (LIRMM) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Jan 2020 15:48 |
Last Modified: | 17 Jan 2020 15:48 |
Status: | Published |
Publisher: | eLife Sciences Publications Ltd |
Identification Number: | 10.7554/eLife.49248.001 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155728 |