Autophagy inhibition-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis.
View/ Open
Date
2019-08-07ICR Author
Author
Hill, C
Li, J
Liu, D
Conforti, F
Brereton, CJ
Yao, L
Zhou, Y
Alzetani, A
Chee, SJ
Marshall, BG
Fletcher, SV
Hancock, D
Ottensmeier, CH
Steele, AJ
Downward, J
Richeldi, L
Lu, X
Davies, DE
Jones, MG
Wang, Y
Type
Journal Article
Metadata
Show full item recordAbstract
Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.
Collections
Subject
Lung
Fibroblasts
Humans
Lung Neoplasms
Transcription Factors
Risk Factors
Cell Differentiation
Aging
Autophagy
Transcription Factor RelA
Idiopathic Pulmonary Fibrosis
Myofibroblasts
Epithelial-Mesenchymal Transition
Primary Cell Culture
Alveolar Epithelial Cells
Snail Family Transcription Factors
Sequestosome-1 Protein
A549 Cells
Research team
Lung Cancer Group
Language
eng
Date accepted
2019-07-18
License start date
2019-08-07
Citation
Cell death & disease, 2019, 10 (8), pp. 591 - ?