Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapies

Abstract

Cystic fibrosis (CF) is a monogenic syndrome determined by over 2000 mutations in the CF Transmembrane Conductance Regulator (CFTR) gene harbored on chromosome 7. In people with CF (PWCF), lung disease is the major determinant of morbidity and mortality and is characterized by a clinical phenotype which differs in the presence of equal mutational assets, indicating that genetic and environmental modifiers play an important role in this variability. Airway inflammation determines the pathophysiology of CF lung disease (CFLD) both at its onset and progression. In this narrative review, we aim to depict the inflammatory process in CF lung, with a particular emphasis on those genetic polymorphisms that could modify the clinical outcome of the respiratory disease in PWCF. The natural history of CF has been changed since the introduction of CFTR modulator therapies in the clinical arena. However, also in this case, there is a patient-to-patient variable response. We provide an overview on inflammatory/immunity gene variants that affect CFLD severity and an appraisal of the effects of CFTR modulator therapies on the inflammatory process in lung disease and how this knowledge may advance the optimization of the management of PWCF.

Keywords: CFTR; CFTR modulator therapy; airway epithelial cells; cystic fibrosis; gene polymorphisms; lung disease; macrophages; neutrophils.

Figure 1

Pictorialization of CFLD pathogenesis and the effect of CFTR modulator therapy. Cellular landscape of CFLD pathogenesis include airway epithelial cells, monocytes/macrophages, and neutrophils. It should be noted that all these cytotypes express a functional CFTR, although it is only represented in airway epithelial cells here. Lack/dysfunction of CFTR in this last cell type leads to increased inflammasome and NF-κB activities with ensuing heightened cytokine production and release. These cytokines and chemokines stimulate neutrophil influx in the airways, a process amplified by the IL-23/IL-17 axis exerted by Th17 cells. Monocytes and macrophages are also hyper-activated in the CF airways, resulting in elevated secretion of cytokines in the blood and airway secretions. CFTR modulator therapies have resulted not only in the CFTR rescue but also in Nerf2 activation in airway epithelial cells. Inflammatory cytokines (TNF-α, IL-17) and bacterial material were shown to enhance CFTR rescue in airway epithelial cells by small-molecules drugs. Although with a certain variability among different dual therapies (ivacaftor/lumacaftor and ivacaftor/tezacaftor) and HEMT, monocytes and macrophages phenotype and functions were modified by CFTR modulators. Finally, HEMT was capable of diminishing neutrophils counts to normality. HEMT: highly effective modulator therapy.