Team's project: Our team, which emerges from the Capeau laboratory, is an internationally recognized research group in the field of cystic fibrosis (CF). This emergence is based on a very positive evolution from a nationwide approach to international research projects. The members of the group have indeed established high-quality international collaborations to identify and study the role of CF modifier genes. They have also studied the inflammatory reaction existing in CF. The team leader, Dr Harriet Corvol is a MD-PhD hospital physician who benefits from an INSERM interface contract and is thus in a good position to lead such a translational research. The projects include in particular a very large integrative genomics/phenomics analysis to investigate the basis of the disease variability as well as the contribution of the inflammatory reaction and endoplasmic reticulum stress to the pathophysiology of CF; in addition, the project also involves the exploration of chloride efflux.
Scientific Context: Cystic fibrosis (CF) is the most common lethal monogenic disorder recessive among Caucasian populations. In CF patients, the lack of CF transmembrane conductance Regulator (CFTR) chloride channels leads to dramatic hydromineral disequilibrium of excretory epithelium. Lung dysfunction is the main cause of mortality and morbidity in cystic fibrosis patients. Infection combined with chronic and sustain inflammation lead to progressive destruction of lung respiratory epithelium and ultimately to death. Glucocorticoids (GC) are molecules with widespread range of potent anti-inflammatory activities. They are commonly used during inflammatory exacerbation in many pulmonary diseases such as asthma, but with deleterious side effects. Moreover, in CF patients they exhibit strong variability in efficiency among them. Moreover, it has been suggested from clinical trials and in vitro studies using cell lines from CF patients that patients and respiratory pulmonary cells subtypes respectively, could be resistant to GC treatments.
Specific project in the team: We hypothesize that this resistance could be explained by the deregulation of intracellular GC pathways. GC act through specific binding to a cytoplasmic receptor (GR) expressed in target cells. The project developed between 2007 and 210 aimed to describe the key steps in GR activation including its phosporylation and nuclear translocation in lung with comparison between CF vs non CF cell lines. The project developed in close collaboration with national and international teams did not show any dysregulation in CF context but enlightened a a cross-talk between pro- and anti-inflammatory pathways (Rebeyrol et al., Cell Signal, 2012). P-38 MAP kinase displays a key role through GR phosphorylation. This work suggests that P38 could be an interesting target to control inflammation in lung diseases. Now, the project is focused on the extracellular events leading to GC delivery on inflammation site. In plasma, 90% of GC is bound to the chaperone protein CBG which regulates its bio-disponibility. CBG also named SERPINA6 belongs to the Serpin family of Serine Protease Inhibitors and is mainly produced by the liver. Recent works enlightened the fact that, more than a simple carrier protein, CBG could also address GC specifically to the inflammation site, thereby modulating the response to GC in an inflammatory context. We show a 10 fold increase in CBG expression in the liver of CF patients. This increase is independent of cirrhosis so directly linked to CF status. The expression of CBG transcripts in the hepatic cell lines is increased in an inflammatory context, but surprisingly, GC has no effect on transcript levels. Such increase in hepatic CBG could contribute to a better delivery of the plasmatic GC. Interestingly, we do not observe an increase of plasmatic CBG. This lack of CBG release from hepatic compartment could explain at least partially the variable answer among CF patients to GC treatments.