The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

Keywords: antagomiRs; antimiRs; biomarkers; circulating miRNAs; cystic fibrosis; genetic disease; miRNA mimics; microRNA; microRNA-targeted therapies.

Figure 1

Airway inflammation in cystic fibrosis. Mutations in CFTR lead to imbalances in fluid and electrolyte homeostasis characterized by the lack of transport of chloride (Cl⁻) and excessive sodium (Na⁺) reabsorption. This impairs mucociliary clearance and increases the viscosity of the mucus, thus promoting chronic bacterial colonization (i.e., by Staphylococcus aureus and Pseudomonas aeruginosa). The resultant shedding of microbial molecules, known as pathogen-associated molecular patterns (PAMPs) (i.e., lipopolysaccharide, LPS), being recognized by the Toll-like receptors (TLRs), constitutively activates the NF-κB and causes the consequent production of inflammatory cytokines (i.e., IL-8), as well as the accumulation of polymorphonuclear neutrophils (PMNs) into the airways. CFTR, cystic fibrosis transmembrane conductance regulator; IL-8, interleukin-8; LPS, lipopolysaccharide; NF-κB, nuclear factor κ light-chain enhancer of activated B cells; PMNs, polymorphonuclear neutrophils; TLRs, toll-like receptors.