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Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD

Hoeke A Baarsma, Wioletta Skronska-Wasek, Kathrin Mutze, Florian Ciolek, Darcy E Wagner, Gerrit John-Schuster, Katharina Heinzelmann, Andreas Günther, Ken Bracke UGent, Maylis Dagouassat, et al. (2017) JOURNAL OF EXPERIMENTAL MEDICINE. 214(1). p.143-163
abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-beta-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-beta, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of beta-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Immunology, Immunology and Allergy
journal title
JOURNAL OF EXPERIMENTAL MEDICINE
J. Exp. Med.
volume
214
issue
1
pages
143 - 163
Web of Science type
Article
Web of Science id
000391123600012
ISSN
0022-1007
1540-9538
DOI
10.1084/jem.20160675
language
English
UGent publication?
yes
classification
A1
additional info
correction published in: J. Exp. Med. (2017) 214(2), 564 ; DOI 10.1084/jem.2016067501052017c
copyright statement
Creative Commons Attribution-ShareAlike 4.0 International Public License (CC BY-SA 4.0)
id
8500523
handle
http://hdl.handle.net/1854/LU-8500523
date created
2017-01-05 14:27:37
date last changed
2017-08-03 06:40:22
@article{8500523,
  abstract     = {Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-beta-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-beta, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of beta-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.},
  author       = {Baarsma, Hoeke A and Skronska-Wasek, Wioletta and Mutze, Kathrin and Ciolek, Florian and Wagner, Darcy E and John-Schuster, Gerrit and Heinzelmann, Katharina and G{\"u}nther, Andreas and Bracke, Ken and Dagouassat, Maylis and Boczkowski, Jorge and Brusselle, Guy and Smits, Ron and Eickelberg, Oliver and Yildirim, Ali {\"O} and K{\"o}nigshoff, Melanie},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  keyword      = {Immunology,Immunology and Allergy},
  language     = {eng},
  number       = {1},
  pages        = {143--163},
  title        = {Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD},
  url          = {http://dx.doi.org/10.1084/jem.20160675},
  volume       = {214},
  year         = {2017},
}

Chicago
Baarsma, Hoeke A, Wioletta Skronska-Wasek, Kathrin Mutze, Florian Ciolek, Darcy E Wagner, Gerrit John-Schuster, Katharina Heinzelmann, et al. 2017. “Noncanonical WNT-5A Signaling Impairs Endogenous Lung Repair in COPD.” Journal of Experimental Medicine 214 (1): 143–163.
APA
Baarsma, H. A., Skronska-Wasek, W., Mutze, K., Ciolek, F., Wagner, D. E., John-Schuster, G., Heinzelmann, K., et al. (2017). Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. JOURNAL OF EXPERIMENTAL MEDICINE, 214(1), 143–163.
Vancouver
1.
Baarsma HA, Skronska-Wasek W, Mutze K, Ciolek F, Wagner DE, John-Schuster G, et al. Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. JOURNAL OF EXPERIMENTAL MEDICINE. 2017;214(1):143–63.
MLA
Baarsma, Hoeke A, Wioletta Skronska-Wasek, Kathrin Mutze, et al. “Noncanonical WNT-5A Signaling Impairs Endogenous Lung Repair in COPD.” JOURNAL OF EXPERIMENTAL MEDICINE 214.1 (2017): 143–163. Print.