TLRs and the Airway Epithelium in the Cystic Fibrosis Lung

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene, encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations disrupt CFTR function within epithelial cells. Although the defect affects ion transport in many organs, the major cause of morbidity and mortality in individuals with CF is the progressive lung disease characterized by inflammation and unremitting bacterial infection with Pseudomonas, Staphylococcus, Haemophilus, Aspergillus and Burkholderia species. Although CF airways exhibit high numbers of immune cells and elevated levels of proinflammatory cytokines, the lung’s innate immune defenses fail to clear bacterial infections. These observations suggest a modified immune response in the CF lung (due to the CFTR mutation and associated secondary alterations of the airway epithelium). Airway epithelial cells not only function as a physical barrier against inhaled pathogens, but also play an important role in innate immune responses of the host. Microorganisms are recognized through a variety of pattern recognition receptors (PRR), mainly Toll-like receptors (TLRs) that are abundantly expressed in airway epithelial cells. TLR activation in a milieu potentially rich in microbial (and endogenous) TLR agonists probably adds to the chronic inflammatory phenotype in CF airway epithelia. Therefore, the expression, function and activation of TLRs in CF airway epithelia have become the focus of intensive research. In this chapter, we give an overview of the current understanding of TLR signaling in CF and its potential role in the pathogenesis of CF lung disease.

Keywords: TLRs, cystic fibrosis, CFTR, therapies.