Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

Heledd H. Jarosz-Griffiths, Thomas Scambler, Chi H. Wong, Samuel Lara-Reyna, Jonathan Holbrook, Fabio Martinon, Sinisa Savic, Paul Whitaker, Christine Etherington, Giulia Spoletini, Ian Clifton, Anil Mehta, Michael F. McDermott, Daniel Peckham (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    24 Citations (Scopus)
    22 Downloads (Pure)

    Abstract

    Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1b, 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-1b 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-1b 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-1b and pro-IL-1b 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.

    Original languageEnglish
    Article numbere54556
    Number of pages16
    JournaleLife
    Volume9
    Early online date2 Mar 2020
    DOIs
    Publication statusPublished - 9 Mar 2020

    Keywords

    • cystic fibrosis
    • human
    • immunology
    • inflammation
    • ivacaftor
    • lumacaftor
    • nlrp3 inflammasome
    • tezacaftor

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