CFTR-Deficiency causes a dysregulation in toll-like receptor-mediated innate immune responses: pathogenetic and therapeutic implications for cystic fibrosis-related liver disease

Cystic Fibrosis (CF) is a common and severe genetic disease, caused by mutations in CFTR, a protein that regulates fluid secretion in a number of organs. In CF patients the disease can be complicated by liver disease (CFLD), a condition that can compromise survival and quality of life of these patients. Unfortunately a cure is not yet available. Defective CFTR function impairs the ability of specialized liver cells to produce bile in the proper amount and quality. This was thought to cause liver damage, however we have found that the recovery of bile secretion is not sufficient to ameliorate liver damage in an experimental model in which CFTR-defective liver cells are exposed to endotoxins. Based on a number of preliminary observations, we hypothesized that lack of CFTR has a profound impact on the defense mechanisms that normally protect the biliary system from infections (innate immunity). In this proposal we will test the novel hypothesis that CFTR participates to the regulation of epithelial innate immunity and that CFLD results from a hyperactive inflammatory response of CFTR-defective biliary cells. Using rodent models, we will also study the therapeutic benefit of interfering with several signaling proteins involved in epithelial innate responses. These studies could lead to novel treatment strategies for CF-related liver disease.