1. Immunology and Inflammation
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ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in Cystic Fibrosis

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Cite this article as: eLife 2019;8:e49248 doi: 10.7554/eLife.49248

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.

Article and author information

Author details

  1. Thomas Scambler

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2468-0218
  2. Heledd H Jarosz-Griffiths

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Samuel Lara-Reyna

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Shelly Pathak

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Chi Wong

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Jonathan Holbrook

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Fabio Martinon

    Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6969-822X
  8. Sinisa Savic

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7910-0554
  9. Daniel Peckham

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7723-1868
  10. Michael F McDermott

    Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
    For correspondence
    M.McDermott@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1015-0745

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.

Reviewing Editor

  1. Jos WM van der Meer, Radboud University Medical Centre, Netherlands

Publication history

  1. Received: June 11, 2019
  2. Accepted: September 17, 2019
  3. Accepted Manuscript published: September 18, 2019 (version 1)
  4. Version of Record published: September 27, 2019 (version 2)

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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