CFTR I556V Variant Exacerbates Cigarette Smoke-Induced Airway Inflammation in COPD by Promoting NLRP3 Inflammasome Activation

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are known to cause cystic fibrosis (CF), a condition that shares several pathophysiological pulmonary features with chronic obstructive pulmonary disease (COPD). Despite these similarities, the relationship between CFTR gene mutations and the risk of developing COPD remains unclear and poorly understood.

We employed exon sequencing to detect CFTR exon variations in 208 COPD patients and 100 control subjects with normal lung function. Subsequently, we applied the adenine base editor system to generate cells and animal models carrying the CFTR chr7:117227874A>G (I556V) variant. Airway epithelial cell models were used to examine the effect of the I556V variant on reactive oxygen species (ROS) levels and mitochondrial membrane potential. Additionally, conventional I556V-CFTR variant (CFTR^V/V ) and wild-type (CFTR^I/I ) mice were exposed to either air or 6 months of cigarette smoke. Immune cell counts were obtained from bronchoalveolar lavage fluid (BALF) samples.

Clinically, we identified seven CFTR variants, with I556V showing a significant association with COPD risk (P = 0.045). Individuals carrying the I556V variant had a 2.12-fold increased risk of developing COPD (OR = 2.12, 95% CI = 1.16-3.86), which increased to 96% after adjusting for age, gender, and smoking status (OR = 1.96, 95% CI = 1.01-3.81). Cells harboring the I556V-CFTR variant exhibited a 27.27% increase in ROS levels and an 85.38% increase in the JC-1 monomer ratio (indicating significant loss of mitochondrial membrane potential) compared to CFTR^I/I cells. In mice, the I556V-CFTR variant led to significant impairment of lung function and exacerbated airway remodeling after 6 months of cigarette smoke (CS) exposure, characterized by a 23.03% increase in airway wall thickness and a 48.40% increase in collagen deposition compared to CS-exposed CFTR^I/I mice. Moreover, there was exacerbated lung inflammation in I556V-CFTR variant mice compared to CFTR^I/I .

In conclusion, the I556V-CFTR variant is a risk factor for COPD. It likely contributes to disease pathogenesis by downregulating CFTR expression, thereby exacerbating oxidative stress and inflammatory responses.