The COPD-Associated Polymorphism Impairs the CFTR Function to Suppress Excessive IL-8 Production upon Environmental Pathogen Exposure

Abstract

COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl- channel, which is invoked in COPD. Despite the increased incidence of CFTR polymorphism R75Q or M470V in COPD patients, the mechanism of how the CFTR variant affects COPD pathogenesis remains unclear. Here, we investigated the impact of CFTR polymorphisms (R75Q, M470V) on the CFTR function in airway epithelial cell models. While wild-type (WT) CFTR suppressed the proinflammatory cytokine production induced by COPD-related pathogens including pyocyanin (PYO), R75Q- or M470V-CFTR failed. Mechanistically, the R75Q- or M470V-CFTR fractional PM activity (FPMA) was significantly lower than WT-CFTR in the presence of PYO. Notably, the CF drug Trikafta corrected the PM expression of R75Q- or M470V-CFTR even upon PYO exposure and consequently suppressed the excessive IL-8 production. These results suggest that R75Q or M470V polymorphism impairs the CFTR function to suppress the excessive proinflammatory response to environmental pathogens associated with COPD. Moreover, Trikafta may be useful to prevent the COPD pathogenesis associated with acquired CFTR dysfunction.

Ligand-based virtual-screening identified a novel CFTR ligand which improves the defective cell surface expression of misfolded ABC transporters

“…The mRNA isolation and real-time quantitative PCR were performed as described previously ( Hinata et al, 2023 ). The following primers were used; CFTR FW primer 5′- AGT​GGA​GGA​AAG​CCT​TTG​GAG​T -3′, CFTR RV primer 5′-ACA​GAT​CTG​AGC​CCA​ACC​TCA-3′, GAPDH FW primer 5′- CAT​GAG​AAG​TAT​GAC​AAC​AGC​CT-3′, GAPDH RV primer 5′- AGT​CCT​TCC​ACG​ATA​CCA​AAG​T-3’.…”

“…The ΔF508-CFTR function assay by short-circuit current measurement was performed as described previously ( Hinata et al, 2023 ). CFBE tet-on ΔF508-CFTR-3HA cells were plated on fibronectin-coated, 12 mm Snapwell filters (Corning, Corning, NY, United States) at a density of 1 × 10 5 cells/cm 2 and treated with 1 μg/mL dox for 4 days.…”