NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
- Ruy Andrade Louzada1,
- Raphaël Corre1,
- Rabii Ameziane El Hassani2,
- Lydia Meziani3,
- Madeleine Jaillet4,
- Aurélie Cazes5,
- Bruno Crestani4,6,7,
- Eric Deutsch3 and
- Corinne Dupuy1⇑
- 1CNRS UMR 8200, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- 2Laboratoire de Biologie des Pathologies Humaines, Université Mohammed V, Faculté des Sciences, Rabat, Morocco
- 3Inserm U1030, Université Paris-Saclay, Gustave Roussy, Villejuif, France
- 4INSERM U1152, Paris, France
- 5Département de Pathologie, Hôpital Bichat, Paris, France
- 6Université Paris-Diderot, LABEX INFLAMEX, Paris, France
- 7Assistance Publique-Hôpitaux de Paris, DHU FIRE, Hôpital Bichat, Paris, France
- Dr Corinne Dupuy, Gustave Roussy, UMR 8200 CNRS, 114 rue Edouard Vaillant; 94805 Villejuif, France. E-mail: corinne.dupuy{at}gustaveroussy.fr
Abstract
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.
Footnotes
This 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.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received October 3, 2019.
- Accepted July 22, 2020.
- Copyright ©ERS 2020