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

Ruy Andrade Louzada, Raphaël Corre, Rabii Ameziane El Hassani, Lydia Meziani, Madeleine Jaillet, Aurélie Cazes, Bruno Crestani, Eric Deutsch, Corinne Dupuy
European Respiratory Journal 2021 57: 1901949; DOI: 10.1183/13993003.01949-2019
Ruy Andrade Louzada
1CNRS UMR 8200, Université Paris-Saclay, Gustave Roussy, Villejuif, France
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Raphaël Corre
1CNRS UMR 8200, Université Paris-Saclay, Gustave Roussy, Villejuif, France
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Rabii Ameziane El Hassani
2Laboratoire de Biologie des Pathologies Humaines, Université Mohammed V, Faculté des Sciences, Rabat, Morocco
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Lydia Meziani
3Inserm U1030, Université Paris-Saclay, Gustave Roussy, Villejuif, France
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Madeleine Jaillet
4INSERM U1152, Paris, France
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Aurélie Cazes
5Département de Pathologie, Hôpital Bichat, Paris, France
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Bruno Crestani
4INSERM U1152, Paris, France
6Université Paris-Diderot, LABEX INFLAMEX, Paris, France
7Assistance Publique-Hôpitaux de Paris, DHU FIRE, Hôpital Bichat, Paris, France
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Eric Deutsch
3Inserm U1030, Université Paris-Saclay, Gustave Roussy, Villejuif, France
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  • ORCID record for Eric Deutsch
Corinne Dupuy
1CNRS UMR 8200, Université Paris-Saclay, Gustave Roussy, Villejuif, France
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  • For correspondence: corinne.dupuy@gustaveroussy.fr
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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 through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (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 (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 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.

Abstract

The data reveal a new function for DUOX1-derived H2O2 as a signalling amplifier of the TGF-1 pathway that causes a chronic long-term fibroblast activation, contributing thus to unrestrained and progressive fibrosis https://bit.ly/39HeEpu

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Author contributions: R.A. Louzada designed and performed experiments, conducted data/statistical analysis and wrote the manuscript; R. Corre performed the experiments and analysed the data; R. Ameziane El Hassani initiated experiments; L. Meziani supervised irradiation, BAL and flow cytometry experiments; M. Jaillet collected human samples; A. Cazes analysed IHC data, B. Crestani and E. Deutsch reviewed the work; C. Dupuy designed and supervised experiments, provided funding and wrote the manuscript.

  • Conflict of interest: R.A. Louzada has nothing to disclose.

  • Conflict of interest: R. Corre has nothing to disclose.

  • Conflict of interest: R. Ameziane El Hassani has nothing to disclose.

  • Conflict of interest: L. Meziani has nothing to disclose.

  • Conflict of interest: M. Jaillet has nothing to disclose.

  • Conflict of interest: A. Cazes has nothing to disclose.

  • Conflict of interest: B. Crestani reports personal fees for lectures from AstraZeneca, grants, personal fees for advisory board work and non-financial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for advisory board work and non-financial support for meeting attendance from BMS, personal fees for advisory board work from Sanofi, outside the submitted work.

  • Conflict of interest: E. Deutsch reports grants and personal fees from Roche Genentech, AstraZeneca/Medimmune, Merck Serono and Boehringer, grants from Servier, BMS, MSD and Amazon AWS, personal fees from Amgen and Accuray, outside the submitted work.

  • Conflict of interest: C. Dupuy has nothing to disclose.

  • Support statement: This work was supported by grants from Institut National du Cancer (INCA), Electricité de France (EDF), Fondation ARC pour la recherche sur le Cancer and GEFLUC. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received October 3, 2019.
  • Accepted July 22, 2020.
  • Copyright ©ERS 2021
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NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
Ruy Andrade Louzada, Raphaël Corre, Rabii Ameziane El Hassani, Lydia Meziani, Madeleine Jaillet, Aurélie Cazes, Bruno Crestani, Eric Deutsch, Corinne Dupuy
European Respiratory Journal Jan 2021, 57 (1) 1901949; DOI: 10.1183/13993003.01949-2019

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NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
Ruy Andrade Louzada, Raphaël Corre, Rabii Ameziane El Hassani, Lydia Meziani, Madeleine Jaillet, Aurélie Cazes, Bruno Crestani, Eric Deutsch, Corinne Dupuy
European Respiratory Journal Jan 2021, 57 (1) 1901949; DOI: 10.1183/13993003.01949-2019
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