Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages.
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| Abstract |
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.
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| Authors | Shan-Shan Liu, Xiao-Xi Lv, Chang Liu, Jie Qi, Yun-Xuan Li, Xu-Peng Wei, Ke Li, Fang Hua, Bing Cui, Xiao-Wei Zhang, Jiao-Jiao Yu, Jin-Mei Yu, Feng Wang, Shuang Shang, Chen-Xi Zhao, Xue-Ying Hou, Zhi-Gang Yao, Ping-Ping Li, Xia Li, Bo Huang, Zhuo-Wei Hu |
| Journal | Immunity (Immunity) Vol. 51 Issue 3 Pg. 522-534.e7 (09 17 2019) ISSN: 1097-4180 [Electronic] United States |
| PMID | 31471107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2019 Elsevier Inc. All rights reserved. |
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