NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue European Respiratory Journal Année : 2021

NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis

Résumé

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-β1/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (H 2 O 2­­ )-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis. Our in vivo data (idiopathic pulmonary fibrosis patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1 +/− and DUOX1 −/− ) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H 2 O 2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation. These findings highlight a role for DUOX1-derived H 2 O 2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.
Fichier principal
Vignette du fichier
article Eur J Resp. 2019 R. Andrade Louzada et al..pdf (185.55 Ko) Télécharger le fichier
Figure 1 VF.pdf (40.37 Mo) Télécharger le fichier
Figure 2 .pdf (183.2 Mo) Télécharger le fichier
Figure 3.pdf (83.64 Mo) Télécharger le fichier
Figure 4.pdf (891.13 Ko) Télécharger le fichier
Figure 5.pdf (689.94 Ko) Télécharger le fichier
Figure 6.pdf (84.41 Ko) Télécharger le fichier
Figure 7.pdf (310.59 Ko) Télécharger le fichier
Figure 8.pdf (1.1 Mo) Télécharger le fichier
Supplementary materiel EJR R. Louzada et al.pdf (1.89 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03445788 , version 1 (25-11-2021)

Identifiants

Citer

Ruy Andrade Louzada, Raphaël Corre, Rabii Ameziane El Hassani, Lydia Meziani, Madeleine Jaillet, et al.. NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis. European Respiratory Journal, 2021, 57 (1), pp.1901949. ⟨10.1183/13993003.01949-2019⟩. ⟨hal-03445788⟩
55 Consultations
244 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More