The Cystic Fibrosis Transmembrane Conductance Receptor Brakes Allergic Airway Inflammation

Abstract

Cystic fibrosis (CF) is a common autosomal recessive disease resulting from mutations of the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Although severe pulmonary neutrophilic inflammation is a primary pathologic feature of CF, more recent studies reveal a role for type 2 inflammation that is characterized by eosinophilia directed by both the innate and adaptive immune systems through ILC2 and CD4+ Th2 cells, respectively. We have published that a clear type endotype exists within CF subjects stratified by Th2 inflammation, defined by increased obstructive pulmonary disease and a distinct phenotypic signature of increased allergic disease, infections, and burden of CF complications. Further, we showed an increased risk of death among CF subjects with type 2 inflammatory signatures compared to CF subjects lacking significant type 2 inflammation. The mechanisms of this heightened type 2 inflammatory signature in CF are still being defined, but it is clear that airway epithelial cells from CFTR-deficient mice have increased expression and release of IL-33, a key activator of ILC2 and Th2 cells, compared to persons with normal CFTR function. Further, there is strong evidence that CF regulates CD4+ Th2 function in a cell-intrinsic fashion. These concepts are explored in this review article.