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Targeting Degradation of the Transcription Factor C/EBPß Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages.

Liu, Shan-Shan; Lv, Xiao-Xi; Liu, Chang; Qi, Jie; Li, Yun-Xuan; Wei, Xu-Peng; Li, Ke; Hua, Fang; Cui, Bing; Zhang, Xiao-Wei; Yu, Jiao-Jiao; Yu, Jin-Mei; Wang, Feng; Shang, Shuang; Zhao, Chen-Xi; Hou, Xue-Ying; Yao, Zhi-Gang; Li, Ping-Ping; Li, Xia; Huang, Bo; Hu, Zhuo-Wei.
Immunity; 51(3): 522-534.e7, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471107
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/EBPß 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-3ß (GSK-3ß) interacted with and phosphorylated A20 to suppress C/EBPß degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3ß interaction accelerated C/EBPß degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3ß-A20-C/EBPß axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.
Selo DaSilva