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.
Highlights
Cystic fibrosis (CF) is characterised by repeated pulmonary infections and disordered innate immune-driven inflammation
We have previously established that monocytes isolated from clinically stable ‘drug-naıve’ CF patients have an increased secretion of IL-18 and IL-1b when compared to healthy control (HC) monocytes
Using monocytes isolated from clinically stable patients homozygous for the common Phe508del CF mutation, we examined whether the in vitro application of clinically approved CFTR modulator combinations (IVA/LUM and IVA/TEZ), could regulate IL-18 and IL-1b levels
Summary
Cystic fibrosis (CF) is characterised by repeated pulmonary infections and disordered innate immune-driven inflammation. The relationship between these two key drivers of disease progression remain poorly understood. We and others have recently provided evidence supporting the hypothesis that the NLRP3-inflammasome is a key regulator of inflammation in CF (McElvaney et al, 2019; Peckham et al, 2017; Scambler et al, 2019). We observed CF-specific increases in IL-18, IL-1b, caspase-1 activity, in addition to ASC-speck release, that were all reversed by pre-treatment with epithelial sodium channel (ENaC) and NLRP3-inflammasome inhibitors (Peckham et al, 2017; Scambler et al, 2019).
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