| First Author | Gardner AI | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100650 | PubMed ID | 33839155 |
| Mgi Jnum | J:313966 | Mgi Id | MGI:6707295 |
| Doi | 10.1016/j.jbc.2021.100650 | Citation | Gardner AI, et al. (2021) Interferon regulatory factor 8 regulates expression of acid ceramidase and infection susceptibility in cystic fibrosis. J Biol Chem :100650 |
| abstractText | Most patients with cystic fibrosis (CF) suffer from acute and chronic pulmonary infections with bacterial pathogens, which often determine their life quality and expectancy. Previous studies have demonstrated a down-regulation of the acid ceramidase in CF epithelial cells resulting in an increase of ceramide and a decrease of sphingosine. Sphingosine kills many bacterial pathogens and the down-regulation of sphingosine seems to determine the infection susceptibility of cystic fibrosis mice and patients. It is presently unknown how deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) connects to a marked down-regulation of the acid ceramidase in human and murine CF epithelial cells. Here, we employed quantitative PCR, western blot analysis and enzyme activity measurements to study the role of IRF8 for acid ceramidase regulation. We report that genetic deficiency or functional inhibition of CFTR/Cftr results in an up-regulation of interferon regulatory factor 8 (IRF8) and a concomitant down-regulation of acid ceramidase expression with CF and an increase of ceramide and a reduction of sphingosine levels in tracheal and bronchial epithelial cells from both human individuals or mice. CRISPR/Cas9- or siRNA-mediated down-regulation of IRF8 prevented changes of acid ceramidase, ceramide and sphingosine in CF epithelial cells and restored resistance to Pseudomonas aeruginosa infections, which is one of the most important and common pathogens in lung infection of patients with CF. These studies indicate that CFTR-deficiency causes a down-regulation of acid ceramidase via up-regulation of IRF8, which is a central pathway to control infection susceptibility of CF cells. |
