FoxO factors are essential for maintaining organ homeostasis by acting as stress sensors in airway epithelial cells

Airway epithelia have the challenging task of maintaining functional and structural homeostasis, even when exposed to various stress factors. Transcription factors of the FoxO family can fulfill this complex task, as they act as integration hubs that translate extrinsic and intrinsic information into a physiologically appropriate response. We could show that FoxO factors in Drosophila, mouse, and human airway epithelial cells (AECs) respond to stressors like hypoxia, temperature, or oxidative stress by nuclear translocation. A complex activation pattern is revealed in human cell culture systems, which differs between individual hFOXO factors and cell types. Studies with Drosophila showed that hypoxia was the only stressor that induced a dfoxo-dependent, local immune response activation. Since Drosophila has only one ortholog of FoxO, it was possible to show that the absence of dfoxo in the airways strongly increases the stress sensitivity of the airways. This stress sensitivity finds its counterpart in mouse models of chronic and acute asthma, with reduced mFoxO expression in the lung, particularly mFoxO1 and mFoxO3A. Finally, it is also reflected in asthma patients who show reduced hFOXO transcripts in their sputum samples. We conclude that active FoxO signaling in AECs is necessary to respond appropriately to stressors. Impaired FoxO signaling limits this ability and thus promotes disease development.