Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

  1. Heledd H Jarosz-Griffiths
  2. Thomas Scambler
  3. Chi H Wong
  4. Samuel Lara-Reyna
  5. Jonathan Holbrook
  6. Fabio Martinon
  7. Sinisa Savic
  8. Paul Whitaker
  9. Christine Etherington
  10. Giulia Spoletini
  11. Ian Clifton
  12. Anil Mehta
  13. Michael F McDermott
  14. Daniel Peckham  Is a corresponding author
  1. University of Leeds, United Kingdom
  2. University of Lausanne, Switzerland
  3. St James's University Hospital, United Kingdom
  4. University of Dundee, United Kingdom

Abstract

Previously we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al., eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Heledd H Jarosz-Griffiths

    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:" 0000-0001-5154-4815
  2. Thomas Scambler

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Chi H Wong

    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:" 0000-0003-2108-1615
  4. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9986-5279
  5. 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.
  6. 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
  7. 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
  8. Paul Whitaker

    Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Christine Etherington

    Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Giulia Spoletini

    Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Ian Clifton

    Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Anil Mehta

    Division of Medical Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Michael F McDermott

    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:" 0000-0002-1015-0745
  14. Daniel Peckham

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    For correspondence
    D.G.Peckham@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7723-1868

Funding

Cystic Fibrosis Trust (SRC009)

  • Daniel Peckham

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human subjects: Patients with CF 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 all participants at the time of the sample collection.

Copyright

© 2020, Jarosz-Griffiths 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.

Metrics

  • 2,588
    views
  • 400
    downloads
  • 87
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

Share this article

https://doi.org/10.7554/eLife.54556

Further reading

    1. Immunology and Inflammation
    Xiaoyu Meng, Yezhang Zhu ... Lie Wang
    Research Article

    FOXP3-expressing regulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in Treg cells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC-finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition. Cxxc1 deletion in Treg cells leads to severe inflammatory disease and spontaneous T cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key Treg functional markers under steady-state conditions, which are essential for the maintenance of Treg cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of Treg program genes in mouse Treg cells, overlapping with FOXP3-binding sites. Given its critical role in Treg cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.

    1. Immunology and Inflammation
    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.