Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages.

Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme A20, causing progressive accumulation of the transcription factor C/EBPβ in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3β (GSK-3β) interacted with and phosphorylated A20 to suppress C/EBPβ degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3β interaction accelerated C/EBPβ degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3β-A20-C/EBPβ axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases. • A20 activity in alveolar macrophages negatively correlates with lung fibrosis • A20 exerts its anti-fibrotic activities by destabilizing C/EBPβ in AMs • GSK-3β interacts with and phosphorylates A20 to impede its activity • Targeting GSK-3β/A20 interaction reduces lung fibrosis by degrading C/EBPβ Dysregulation of the ubiquitin-editing enzyme A20 contributes to the development of several human inflammatory diseases. Liu et al. demonstrate that suppression of A20 enzymatic activity in alveolar macrophages promotes lung fibrosis by reducing transcriptional factor C/EBPβ degradation and enhancing targeted gene expression, which directs the profibrotic phenotype of macrophages. [ABSTRACT FROM AUTHOR]