Journal
IMMUNITY
Volume 51, Issue 3, Pages 522-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2019.06.014
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Funding
- National Key R&D Program of China [2017YFA0205400]
- National Natural Science Foundation of China [81530093, 81773781, 81803604, 81503128, 81622010, 81770800]
- Chinese Academy of Medical Sciences (CAMS) Central Public-Interest Scientific Institution Basal Research Fund (Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, CAMS Key Lab) [2017PT31046]
- CAMS Innovation Fund for Medical Sciences [2016-I2M-1-007, 2016-I2M-1-008, 2016-I2M-1-010, 2016-I2M-3-008, 2016-I2M-1011, 2016-I2M-4-001]
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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.
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