Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD - Archive ouverte HAL Access content directly
Journal Articles Journal of Experimental Medicine Year : 2017

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

(1) , (1) , (1) , (1) , (1) , (1) , (2) , (3) , (4) , (4) , (3) , (5) , (1) , (1) , (1)
1
2
3
4
5

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–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.
Fichier principal
Vignette du fichier
jem_20160675.pdf (3.56 Mo) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

inserm-03573221 , version 1 (14-02-2022)

Identifiers

Cite

Hoeke Baarsma, Kathrin Mutze, Florian Ciolek, Darcy Wagner, Gerrit John-Schuster, et al.. Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD. Journal of Experimental Medicine, 2017, 214 (1), pp.143-163. ⟨10.1084/jem.20160675⟩. ⟨inserm-03573221⟩

Collections

INSERM IMRB UPEC
14 View
12 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More