Cargando…

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

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–β-catenin signaling is linked to impa...

Descripción completa

Detalles Bibliográficos
Autores principales: Baarsma, Hoeke A., Skronska-Wasek, Wioletta, Mutze, Kathrin, Ciolek, Florian, Wagner, Darcy E., John-Schuster, Gerrit, Heinzelmann, Katharina, Günther, Andreas, Bracke, Ken R., Dagouassat, Maylis, Boczkowski, Jorge, Brusselle, Guy G., Smits, Ron, Eickelberg, Oliver, Yildirim, Ali Ö., Königshoff, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206496/
https://www.ncbi.nlm.nih.gov/pubmed/27979969
http://dx.doi.org/10.1084/jem.20160675
_version_ 1782490269034217472
author Baarsma, Hoeke A.
Skronska-Wasek, Wioletta
Mutze, Kathrin
Ciolek, Florian
Wagner, Darcy E.
John-Schuster, Gerrit
Heinzelmann, Katharina
Günther, Andreas
Bracke, Ken R.
Dagouassat, Maylis
Boczkowski, Jorge
Brusselle, Guy G.
Smits, Ron
Eickelberg, Oliver
Yildirim, Ali Ö.
Königshoff, Melanie
author_facet Baarsma, Hoeke A.
Skronska-Wasek, Wioletta
Mutze, Kathrin
Ciolek, Florian
Wagner, Darcy E.
John-Schuster, Gerrit
Heinzelmann, Katharina
Günther, Andreas
Bracke, Ken R.
Dagouassat, Maylis
Boczkowski, Jorge
Brusselle, Guy G.
Smits, Ron
Eickelberg, Oliver
Yildirim, Ali Ö.
Königshoff, Melanie
author_sort Baarsma, Hoeke A.
collection PubMed
description 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–β-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-β, 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 β-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.
format Online
Article
Text
id pubmed-5206496
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-52064962017-07-01 Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD Baarsma, Hoeke A. Skronska-Wasek, Wioletta Mutze, Kathrin Ciolek, Florian Wagner, Darcy E. John-Schuster, Gerrit Heinzelmann, Katharina Günther, Andreas Bracke, Ken R. Dagouassat, Maylis Boczkowski, Jorge Brusselle, Guy G. Smits, Ron Eickelberg, Oliver Yildirim, Ali Ö. Königshoff, Melanie J Exp Med Research Articles 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–β-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-β, 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 β-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. The Rockefeller University Press 2017-01 /pmc/articles/PMC5206496/ /pubmed/27979969 http://dx.doi.org/10.1084/jem.20160675 Text en © 2017 Baarsma et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License(Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Baarsma, Hoeke A.
Skronska-Wasek, Wioletta
Mutze, Kathrin
Ciolek, Florian
Wagner, Darcy E.
John-Schuster, Gerrit
Heinzelmann, Katharina
Günther, Andreas
Bracke, Ken R.
Dagouassat, Maylis
Boczkowski, Jorge
Brusselle, Guy G.
Smits, Ron
Eickelberg, Oliver
Yildirim, Ali Ö.
Königshoff, Melanie
Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title_full Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title_fullStr Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title_full_unstemmed Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title_short Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
title_sort noncanonical wnt-5a signaling impairs endogenous lung repair in copd
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206496/
https://www.ncbi.nlm.nih.gov/pubmed/27979969
http://dx.doi.org/10.1084/jem.20160675
work_keys_str_mv AT baarsmahoekea noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT skronskawasekwioletta noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT mutzekathrin noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT ciolekflorian noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT wagnerdarcye noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT johnschustergerrit noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT heinzelmannkatharina noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT guntherandreas noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT brackekenr noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT dagouassatmaylis noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT boczkowskijorge noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT brusselleguyg noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT smitsron noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT eickelbergoliver noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT yildirimalio noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd
AT konigshoffmelanie noncanonicalwnt5asignalingimpairsendogenouslungrepairincopd