Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways.

Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes. [Display omitted] • Chronic epithelial immune activation leads to structural changes in the airways • Activation of JNK signaling via TAK1 mediates this airway remodeling • FoxO acts downstream of JNK signaling in inducing this airway remodeling • NF-κB factors are of minor relevance for this response Chronic activation of the immune system in the Drosophila airway epithelium induces massive structural changes of the organ. These structural changes are mediated by a bifurcation of the IMD pathway at the level of TAK1, involving the JNK pathway and subsequent activation of the transcription factor FoxO. [ABSTRACT FROM AUTHOR]