Revisiting the Role of Leukocytes in Cystic Fibrosis

Abstract

Cystic fibrosis in characterized by pulmonary bacterial colonization and hyperinflammation. Lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells of patients with CF express functional CFTR and are directly affected by altered CFTR expression/function, impairing their ability to resolve infections and inflammation. However, the mechanism behind and the contribution of leukocytes in the pathogenesis of CF are still poorly characterized. The recent clinical introduction of specific CFTR modulators added an important tool not only for the clinical management of the disease but also to the investigation of the pathophysiological mechanisms related to CFTR dysfunction and dysregulated immunity. These drugs treat the basic defect in cystic fibrosis (CF) by increasing CFTR function with improvement of lung function and quality of life, and may improve clinical outcomes also by correcting the dysregulated immune function that characterizes CF. Measure of CFTR function, protein expression profiling and several omics methods were used to identify molecular changes in freshly isolated leukocytes of CF patients, highlighting two roles of leukocytes in CF: one more generally related to the mechanism(s) causing immune dysregulation in CF and unresolved inflammation, and another more applicative role, which identifies in myeloid cells, an important tool predictive of the therapeutic response of CF patients. In this review we will summarize available data on CFTR expression and function in leukocyte populations and will discuss potential clinical applications based on available data.

Respiratory Infection and Inflammation in Cystic Fibrosis: A Dynamic Interplay among the Host, Microbes, and Environment for the Ages

“…Notably, the effect of CFTR dysfunction may differ in nonepithelial cells. Neutrophils in CF patients (F508del) were observed to have a prolonged survival and reduced degranulation, affecting the ability to kill bacteria effectively [ 65 ].…”

Cystic Fibrosis Bone Disease: The Interplay between CFTR Dysfunction and Chronic Inflammation

“…Cystic fibrosis is associated with a hyperinflammatory state due to the conjugation of chronic lung infection, epithelial dysfunction and innate and adaptative immune dysregulation [ 126 , 127 ]. Alveolar macrophages and neutrophils accumulate in the lungs of cystic fibrosis patients [ 126 ].…”

Role of innate immunity and systemic inflammation in cystic fibrosis disease progression

“…Moreover, consequences of the absence of basal CFTR function varies between different cell types in terms of its metabolism, location, and function. Cells being fundamental units of the body, the outcome could vary widely from tissue to tissue and from organ to organ depending on the type, number, and location of CFTR-expressing cells present [ 26 , 27 ]. Since all organ systems are interconnected, CF patients often manifest the overall pathophysiological outcome [ 2 , 19 ].…”