CFTR controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity

• Published in: Hepatology (Baltimore, Md.) Vol. 64; no. 6; pp. 2118 - 2134
• Main Authors: Fiorotto, Romina, Villani, Ambra, Kourtidis, Antonis, Scirpo, Roberto, Amenduni, Mariangela, Geibel, Peter J., Cadamuro, Massimilano, Spirli, Carlo, Anastasiadis, Panos Z., Strazzabosco, Mario
• Format: Journal Article
• Language: English
• Published: 27-10-2016
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.28817

In the liver, CFTR regulates bile secretion and other functions at the apical membrane of biliary epithelial cells (i.e cholangiocytes). CF-related liver disease (CFLD) is a major cause of death in patients with CF. CFTR dysfunction affects innate immune pathways, generating a para-inflammatory status in the liver, and other epithelia. This study investigates the mechanisms linking CFTR to TLR4 activity. We found that CFTR is associated in a multi-protein complex at the apical membrane of normal mouse cholangiocytes, with proteins that negatively control Src activity. In CFTR-defective cholangiocytes, Src tyrosine kinase self-activates and phosphorylates TLR4, resulting in activation of NF-κB, and increased pro-inflammatory cytokines production in response to endotoxins. This Src/NF-κB-dependent inflammatory process attracts inflammatory cells, but also generates changes in the apical junctional complex and loss of epithelial barrier function. Inhibition of Src decreased the inflammatory response of CF-cholangiocytes to LPS, rescued the junctional defect
in-vitro
and significantly attenuated endotoxin-induced biliary damage and inflammation
in vivo
(Cftr-KO mice).