RFFL inhibition increases cell surface CFTR and reduces IL-8 production in airway epithelial cells upon COPD-associated environmental pathogen exposure.

Chronic exposure to environmental pathogens and pollutants can impair CFTR chloride channel function, contributing to chronic obstructive pulmonary disease (COPD). Our previous study demonstrated that pyocyanin (PYO), a COPD-associated pathogen factor, significantly reduces the functional expression of R75Q- or M470V-CFTR, two CFTR polymorphisms found in COPD patients, leading to increased IL-8 production in airway epithelial cells (AEC). In this study, we report that inhibition of RFFL, a ubiquitin ligase that targets CFTR mutants for removal from the plasma membrane (PM), mitigates excessive IL-8 production in AECs expressing R75Q- or M470V-CFTR, even in the presence of PYO. RFFL knockdown (KD) enhanced the functional PM expression of R75Q- or M470V-CFTR under PYO exposure, although it did not prevent PYO-induced CFTR downregulation. Our results indicate that RFFL likely regulates constitutive IL-8 production independently of CFTR, while also modulating pathogen-induced IL-8 expression through a CFTR-dependent mechanism. This highlights the potential of RFFL inhibitors to enhance CFTR function and reduce IL-8 secretion, even amid chronic exposure to environmental pathogens and pollutants, underscoring RFFL inhibition as a promising therapeutic approach for COPD management.