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.
Keywords: E3 ligase; UPS; inflammation; lung injury; protein-protein interaction; pulmonary fibrosis; ubiquitination; α-helical peptide.
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