JNK integrates immune and stress signals to balance apoptosis and proliferation in airway progenitors
Shi, L.; Niu, X.; Zhang, K.; Stein, K.; Heine, H.; Hammel, J. U.; Bruchhaus, I.; Krauss-Etschmann, S.; Bossen, J.; Roeder, T.
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Chronic inflammation disrupts epithelial regeneration, yet how immune signaling reprograms progenitor fate remains unclear. Using the Drosophila airway as a model of epithelial remodeling, we identify the c-Jun N-terminal kinase (JNK) pathway as a central integrator of immune and stress cues that balances apoptosis and compensatory proliferation in airway progenitors. Persistent activation of the innate immune IMD pathway induces simultaneous cell death and proliferation through a non-canonical route that bypasses NF-{kappa}B/Relish and instead engages JNK. Downstream, distinct transcriptional modules orchestrate these divergent fates: Foxo and AP-1 drive apoptosis, whereas the ETS factor Ets21C mediates proliferation. Genetic inhibition of JNK or its effectors restores progenitor homeostasis, while constitutive activation recapitulates inflammation-induced tissue remodeling. These responses are cell-autonomous, revealing that airway progenitors actively interpret immune and stress signals to determine their fate. Collectively, our findings uncover a modular signaling architecture that links inflammation to regeneration and highlight conserved JNK-dependent transcriptional programs as potential therapeutic targets to prevent progenitor exhaustion in chronic airway disease.
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