Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis
Research output: Contribution to journal › Article › peer-review
- University of Leeds
- Leeds Teaching Hospitals NHS Trust
- University of Dundee
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.
|Publication status||Published - 2 Mar 2020|
- Adult, Aminophenols/administration & dosage, Aminopyridines/administration & dosage, Benzodioxoles/administration & dosage, Cystic Fibrosis/drug therapy, Cystic Fibrosis Transmembrane Conductance Regulator/drug effects, Cytokines/metabolism, Down-Regulation, Drug Therapy, Combination, Female, Humans, Indoles/administration & dosage, Inflammation/diet therapy, Interleukin-18/blood, Interleukin-1beta/blood, Male, Monocytes/drug effects, Quinolones/administration & dosage, Tumor Necrosis Factor-alpha/blood, Young Adult