Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis
- University of Leeds, United Kingdom
- University of Lausanne, Switzerland
- St James's University Hospital, United Kingdom
- 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
Heledd H Jarosz-Griffiths
Michael F McDermott
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.
Reviewing Editor
- Jos WM van der Meer, Radboud University Medical Centre, Netherlands
Version history
- Received: January 3, 2020
- Accepted: February 28, 2020
- Accepted Manuscript published: March 2, 2020 (version 1)
- Version of Record published: March 9, 2020 (version 2)
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.
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Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis
eLife 9:e54556.
https://doi.org/10.7554/eLife.54556
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