RRC ID 57610
Author Liu SS, Lv XX, Liu C, Qi J, Li YX, Wei XP, Li K, Hua F, Cui B, Zhang XW, Yu JJ, Yu JM, Wang F, Shang S, Zhao CX, Hou XY, Yao ZG, Li PP, Li X, Huang B, Hu ZW.
Title Targeting Degradation of the Transcription Factor C/EBPβ Reduces Lung Fibrosis by Restoring Activity of the Ubiquitin-Editing Enzyme A20 in Macrophages.
Journal Immunity
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.
Volume 51(3)
Pages 522-534.e7
Published 2019-9-17
DOI 10.1016/j.immuni.2019.06.014
PII S1074-7613(19)30284-5
PMID 31471107
MeSH Animals CCAAT-Enhancer-Binding Protein-beta / metabolism* Cell Line Glycogen Synthase Kinase 3 beta / metabolism HEK293 Cells Humans Inflammation / metabolism Macrophages / metabolism* Mice Mice, Inbred C57BL Phosphorylation / physiology Pulmonary Fibrosis / metabolism* Signal Transduction / physiology Transcription Factors / metabolism* Ubiquitin / metabolism* Ubiquitin-Protein Ligases / metabolism Ubiquitination / physiology Up-Regulation / physiology
IF 21.522
Times Cited 3
Mice RBRC05494