Highly Effective Modulator Therapies Restore Neutrophil Dysfunction in People with Cystic Fibrosis

Cystic fibrosis (CF) is a common genetic disease caused by a defective CF-transmembrane conductance regulator (CFTR). People with CF (pwCF) are prone to develop infections by opportunistic pathogens, including Burkholderia cenocepacia, leading to chronic inflammation. Neutrophils release granular proteins and oxidative products that contribute to tissue damage. CFTR modulators are a new treatment for pwCF aiming to correct the subcellular location and function of the CFTR ion channel. The triple modulator combination of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) or Trikafta® has significantly improved clinical symptoms and overall provided a better quality of life for pwCF. The mechanism by which CFTR modulators help to restore the antimicrobial functions of neutrophils is unknown. The present study demonstrated that neutrophils functionally express CFTR and revealed how ETI modifies subcellular CFTR trafficking in CF neutrophils. In addition, ETI treatment reduced intracellular chloride levels in human neutrophils, indicating activation of CFTR-dependent chloride efflux. Finally, ETI treatment also re-established the intracellular antimicrobial killing of CF neutrophils by potentiating NADPH oxidase activity and improved trapping microbes by enhancing the production of Neutrophil Extracellular Traps (NETs). Together, our findings suggest that CFTR has an essential role in controlling neutrophil functions and CFTR modulators help restore the antimicrobial functions of neutrophils from pwCF.