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 language | English |
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Article number | e54556 |
Number of pages | 16 |
Journal | eLife |
Volume | 9 |
Early online date | 2 Mar 2020 |
DOIs | |
Publication status | Published - 9 Mar 2020 |
Keywords
- cystic fibrosis
- human
- immunology
- inflammation
- ivacaftor
- lumacaftor
- nlrp3 inflammasome
- tezacaftor
ASJC Scopus subject areas
- General Neuroscience
- General Immunology and Microbiology
- General Biochemistry,Genetics and Molecular Biology