Balanced JAK/STAT signaling is critical to maintain the functional and structural integrity of the Drosophila respiratory epithelium

Signals mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway play a central role in maintaining homeostasis in a multitude of tissues. A large number of studies have shown that this role is particularly prominent in the lungs. Deregulation of the JAK/STAT signaling pathway is causally linked with various, mostly chronic, lung diseases, including lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular framework that explains how deregulated JAK/STAT signaling gives rise to pathogenic states, we used the fruit fly Drosophila as a model. While the JAK/STAT pathway is characterized by high structural diversity and complexity in vertebrates, it is relatively simple in Drosophila. The JAK/STAT pathway was active in almost all respiratory epithelial cells of larvae and adult flies. Stressful stimuli, such as cigarette smoke, evoked strong and regionalized activation of the JAK/STAT pathway, which was most likely driven by the concurrently induced ligand Unpaired 2. Inhibition of JAK/STAT signaling induced apoptotic processes in epithelial cells. The aforementioned chronic lung diseases are associated with increased activity of the JAK/STAT pathway and are treated with specific JAK inhibitors. Therefore, we investigated the effects of increased JAK/STAT signaling in the respiratory epithelium of Drosophila. Ectopic activation of the JAK/STAT pathway led to premature death at the larval or pupal stage. Furthermore, it induced major structural changes in epithelial cells, which almost completely lost their typical characteristics. These structural changes led to considerable thickening of the epithelium, substantial narrowing of the air-conducting space, and disruption of the tracheal epicuticular structure. Pharmacological interference of JAK/STAT signaling reverted this phenotype. Activation of the JAK/STAT pathway also affected vesicle-mediated transport, which led to erroneous trafficking of typical junction proteins. In summary, these results demonstrate that balanced JAK/STAT signaling is essential for the normal functionality of the respiratory epithelium and thus the entire organ. A basal level of JAK/STAT signaling is required for cellular processes such as growth and division. However, chronic overactivation of this signaling leads to massive structural changes that are closely related to pathologies typically seen in chronic inflammatory lung diseases.