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/EBP beta 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-3 beta (GSK-3 beta) interacted with and phosphorylated A20 to suppress C/EBP beta degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3 beta interaction accelerated C/EBP beta degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3 beta-A20-C/EBP beta axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.