Gene expression profiles of alveolar macrophages isolated from wild type (WT) and A20 conditional knockout mice after BLM exposure

Although recent progressions have provided significant mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), few of anti-PF therapeutics show certain promise for this devastating disease. Chronic or repeated lung injury results in chronic inflammation, which functions as a major driven force to promote PF development. Here we report that chronic lung injury inactivates ubiquitin-modifying enzyme A20 to cause a progressive accumulation of transcription factor C/EBPb in macrophages, which produce a number of pro-fibrotic factors to promote PF development. Elevated GSK-3b expression, in response to chronic lung injury, interacts with and phosphorylates A20 to suppress C/EBPb degradation in macrophages. Enforced expression of A20 or pharmacological acceleration of C/EBPb degradation by a peptide restores the A20 activity and provides potent therapeutic efficacy against experimental PF. Our studies reveal a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in alveolar macrophages, by targeting which can treat PF and fibroproliferative lung diseases. Overall design: mRNA profiles of alveolar macrophages from WT and A20 conditional knockout mice were generated by deep sequencing, in triplicate, using Illumina Hiseq.