ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in Cystic Fibrosis
- University of Leeds, United Kingdom
- University of Lausanne, Switzerland
Abstract
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-1b, 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 b-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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Michael F McDermott
Funding
Cystic Fibrosis Trust (SRC009)
- Heledd H Jarosz-Griffiths
- Chi Wong
- Jonathan Holbrook
- Fabio Martinon
- Sinisa Savic
- Daniel Peckham
University of Leeds (110 University Scholarship)
- Thomas Scambler
Consejo Nacional de Ciencia y Tecnología (CONACyT)
- Samuel Lara-Reyna
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Patients with CF, systemic autoinflammatory diseases (SAID), non-CF bronchiectasis (NCFB) and healthy controls (HC) were recruited from the Department of Respiratory Medicine and Research laboratories at the Wellcome Trust Benner Building at St James's Hospital. The study was approved by Yorkshire and The Humber Research Ethics Committee (17/YH/0084). Informed written consent was obtained from allparticipants at the time of the sample collection.
Copyright
© 2019, Scambler et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in Cystic Fibrosis
eLife 8:e49248.
https://doi.org/10.7554/eLife.49248
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