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Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

Heledd H Jarosz-Griffiths1,2, Thomas Scambler2,3, Chi H Wong2,3

  • 1Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.

Elife
|March 3, 2020
PubMed

Insights

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators reduce the exaggerated inflammatory response in cystic fibrosis patients. These drugs decrease key inflammatory markers, suggesting potential clinical benefits beyond improved CFTR function.

Area of Science:

  • Immunology
  • Pharmacology
  • Genetics

Background:

  • Patients with cystic fibrosis (CF) exhibit an enhanced NLRP3-inflammasome signature, characterized by increased IL-18, IL-1β, caspase-1 activity, and ASC speck release.
  • This exaggerated inflammatory response contributes to CF pathology.

Purpose of the Study:

  • To investigate the anti-inflammatory effects of CFTR modulators in cystic fibrosis.
  • To determine if CFTR modulators can downregulate the enhanced NLRP3-inflammasome signature observed in CF patients.

Main Methods:

  • In vitro studies using CF monocytes treated with ivacaftor/lumacaftor or ivacaftor/tezacaftor.
  • In vivo assessment of adults with CF receiving CFTR modulator treatments over three months.
  • Measurement of serum and peripheral blood mononuclear cell (PBMC) inflammatory markers (IL-18, IL-1β, TNF, IL-10, caspase-1 activity) following stimulation.

Main Results:

  • In vitro, ivacaftor/lumacaftor and ivacaftor/tezacaftor reduced IL-18 in CF monocytes. Ivacaftor/tezacaftor also reduced IL-1β.
  • In adults with CF, serum IL-18 and TNF significantly decreased with both treatments. IL-1β declined only with ivacaftor/tezacaftor.
  • Both CFTR modulator combinations significantly decreased IL-18, TNF, and caspase-1 activity in stimulated PBMCs, while increasing IL-10. Ivacaftor/tezacaftor alone reduced IL-1β and pro-IL-1β mRNA.

Conclusions:

  • CFTR modulator combinations demonstrate potent anti-inflammatory properties by downregulating key components of the NLRP3-inflammasome pathway.
  • These anti-inflammatory effects, in addition to restoring CFTR function, may contribute to improved clinical outcomes in cystic fibrosis patients.
Keywords:
cystic fibrosishumanimmunologyinflammationivacaftorlumacaftornlrp3 inflammasometezacaftor

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