RT Journal Article
SR Electronic
T1 NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1901949
DO 10.1183/13993003.01949-2019
A1 Ruy Andrade Louzada
A1 Raphaël Corre
A1 Rabii Ameziane El Hassani
A1 Lydia Meziani
A1 Madeleine Jaillet
A1 Aurélie Cazes
A1 Bruno Crestani
A1 Eric Deutsch
A1 Corinne Dupuy
YR 2020
UL http://erj.ersjournals.com/content/early/2020/07/23/13993003.01949-2019.abstract
AB 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 (ROS) through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular H2O2-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 (IPF 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 also 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 H2O2 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 H2O2 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Louzada has nothing to disclose.Conflict of interest: Dr. CORRE has nothing to disclose.Conflict of interest: Dr. Ameziane El Hassani has nothing to disclose.Conflict of interest: Dr. MEZIANI has nothing to disclose.Conflict of interest: Dr. Jaillet has nothing to disclose.Conflict of interest: Dr. Cazes has nothing to disclose.Conflict of interest: Dr. CRESTANI reports personal fees from Astra Zeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from BMS, personal fees from Sanofi, grants, personal fees and non-financial support from Roche, outside the submitted work.Conflict of interest: Dr. DEUTSCH reports grants and personal fees from ROCHE GENENTECH, grants from SERVIER, grants and personal fees from ASTRAZENECA/Medimmune, grants and personal fees from MERCK SERONO, grants from BMS, grants from MSD, personal fees from AMGEN, personal fees from Accuray, grants and personal fees from Boehringer, grants from Amazon AWS, outside the submitted work.Conflict of interest: Dr. DUPUY has nothing to disclose.