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)

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    11 Citations (Scopus)
    50 Downloads (Pure)


    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
    Pages (from-to)1-16
    Number of pages16
    Early online date2 Mar 2020
    Publication statusPublished - 9 Mar 2020


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

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