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Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease

Delphine Beaulieu, Aya Attwe, Marielle Breau, Larissa Lipskaia, Elisabeth Marcos, Emmanuelle Born, Jin Huang, Shariq Abid, Geneviève Derumeaux, Amal Houssaini, Bernard Maitre, Marine Lefevre, Nora Vienney, Philippe Bertolino, Sara Jaber, Hiba Noureddine, Delphine Goehrig, David Vindrieux, David Bernard, Serge Adnot
European Respiratory Journal 2021 58: 2000752; DOI: 10.1183/13993003.00752-2020
Delphine Beaulieu
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
6These two authors contributed equally
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Aya Attwe
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
2Environmental Health Research Laboratory (EHRL), Faculty of Sciences V, Lebanese University, Nabatieh, Lebanon
6These two authors contributed equally
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Marielle Breau
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Larissa Lipskaia
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Elisabeth Marcos
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Emmanuelle Born
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Jin Huang
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Shariq Abid
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Geneviève Derumeaux
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Amal Houssaini
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Bernard Maitre
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Marine Lefevre
3Département Anatomopathologie, Institut Mutualiste Montsouris, Paris, France
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Nora Vienney
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
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Philippe Bertolino
4Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France
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  • ORCID record for Philippe Bertolino
Sara Jaber
4Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France
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Hiba Noureddine
2Environmental Health Research Laboratory (EHRL), Faculty of Sciences V, Lebanese University, Nabatieh, Lebanon
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Delphine Goehrig
4Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France
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David Vindrieux
4Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France
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David Bernard
4Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France
7These two authors are joint senior authors
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Serge Adnot
1INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France
5Institute for Lung Health, University of Giessen, Giessen, Germany
7These two authors are joint senior authors
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  • For correspondence: serge.adnot@inserm.fr
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Abstract

Background Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis.

Methods We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knockdown, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the Pla2r1 gene (LV-PLA2R1 mice).

Results We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old PLA2R1-TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment.

Conclusions Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.

Abstract

PLA2R1 is a potent regulator of lung cell senescence in COPD, with JAK/STAT signalling as a major effector. Inhibition of JAK1/2 attenuates PLA2R1-induced lung alterations in murine models and so may represent a promising therapeutic approach for COPD. http://bit.ly/3i7yT3H

Footnotes

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

  • Data availability: The data that support the findings of this study are available from the corresponding author upon request.

  • Author contributions: D. Beaulieu, A. Attwe and S. Abid: conception and design, acquisition, analysis and interpretation of data, and drafting of the manuscript. M. Breau, E. Marcos, E. Born, J. Huang, A. Houssaini, N. Vienney, P. Bertolino, S. Jaber, D. Goehrig and D. Vindrieux: acquisition, analysis and interpretation of data. L. Lipskaia: conception and design, and acquisition, analysis and interpretation of data. G. Derumeaux, B. Maitre, M. Lefevre and H. Noureddine: analysis and interpretation of data, and revision of the manuscript. D. Bernard and S. Adnot: conception and design, analysis and interpretation of data, and drafting of the manuscript.

  • Conflict of interest: D. Beaulieu has nothing to disclose.

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

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

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

  • Conflict of interest: E. Marcos has nothing to disclose.

  • Conflict of interest: E. Born has nothing to disclose.

  • Conflict of interest: J. Huang has nothing to disclose.

  • Conflict of interest: S. Abid has nothing to disclose.

  • Conflict of interest: G. Derumeaux has nothing to disclose.

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

  • Conflict of interest: B. Maitre has nothing to disclose.

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

  • Conflict of interest: N. Vienney has nothing to disclose.

  • Conflict of interest: P. Bertolino has nothing to disclose.

  • Conflict of interest: S. Jaber has nothing to disclose.

  • Conflict of interest: H. Noureddine has nothing to disclose.

  • Conflict of interest: D. Goehrig has nothing to disclose.

  • Conflict of interest: D. Vindrieux has nothing to disclose.

  • Conflict of interest: D. Bernard has nothing to disclose.

  • Conflict of interest: S. Adnot has nothing to disclose.

  • Support statement: This study was supported by grants from the INSERM, Délégation à la Recherche Clinique de l'AP-HP–FHU SENEC, Fondation pour la Recherche Médicale (FRM), Legs Poix, Agence Nationale pour la Recherche (ANR) and Institut National Du Cancer (INCA). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received March 18, 2020.
  • Accepted December 28, 2020.
  • Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease
Delphine Beaulieu, Aya Attwe, Marielle Breau, Larissa Lipskaia, Elisabeth Marcos, Emmanuelle Born, Jin Huang, Shariq Abid, Geneviève Derumeaux, Amal Houssaini, Bernard Maitre, Marine Lefevre, Nora Vienney, Philippe Bertolino, Sara Jaber, Hiba Noureddine, Delphine Goehrig, David Vindrieux, David Bernard, Serge Adnot
European Respiratory Journal Aug 2021, 58 (2) 2000752; DOI: 10.1183/13993003.00752-2020

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Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease
Delphine Beaulieu, Aya Attwe, Marielle Breau, Larissa Lipskaia, Elisabeth Marcos, Emmanuelle Born, Jin Huang, Shariq Abid, Geneviève Derumeaux, Amal Houssaini, Bernard Maitre, Marine Lefevre, Nora Vienney, Philippe Bertolino, Sara Jaber, Hiba Noureddine, Delphine Goehrig, David Vindrieux, David Bernard, Serge Adnot
European Respiratory Journal Aug 2021, 58 (2) 2000752; DOI: 10.1183/13993003.00752-2020
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