TRIB3‒GSK-3ß interaction promotes lung fibrosis and serves as a potential therapeutic target.

ABSTRACT

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3ß (GSK-3ß) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPß) in alveolar macrophages (AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3ß and stabilized GSK-3ß from ubiquitination and degradation. Elevated GSK-3ß expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBPß and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBPß, in turn, increased the transcription of TRIB3 and GSK-3ß, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3ß interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3ß‒A20‒C/EBPß in AMs, which represents a target that may provide a promising treatment strategy for PF.