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Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis

Laura Pandolfi, View ORCID ProfileSara Bozzini, Vanessa Frangipane, View ORCID ProfileElena Percivalle, Ada De Luigi, View ORCID ProfileMartina Bruna Violatto, Gianluca Lopez, View ORCID ProfileElisa Gabanti, Luca Carsana, Maura D’Amato, View ORCID ProfileMonica Morosini, View ORCID ProfileMara De Amici, Manuela Nebuloni, Tommaso Fossali, Riccardo Colombo, View ORCID ProfileLaura Saracino, Veronica Codullo, Massimiliano Gnecchi, View ORCID ProfilePaolo Bigini, Fausto Baldanti, Daniele Lilleri, Federica Meloni
doi: https://doi.org/10.1101/2020.11.09.374769
Laura Pandolfi
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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  • For correspondence: l.pandolfi@smatteo.pv.it
Sara Bozzini
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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  • ORCID record for Sara Bozzini
Vanessa Frangipane
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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Elena Percivalle
2Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
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  • ORCID record for Elena Percivalle
Ada De Luigi
3Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, Italy
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Martina Bruna Violatto
3Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, Italy
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  • ORCID record for Martina Bruna Violatto
Gianluca Lopez
4Pathology Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milano, Milano, Italy
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Elisa Gabanti
2Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
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  • ORCID record for Elisa Gabanti
Luca Carsana
4Pathology Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milano, Milano, Italy
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Maura D’Amato
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
5Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy
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Monica Morosini
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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Mara De Amici
6Laboratory of Immuno Allergology Clinical Chemistry and Pediatrics Clinic, Foundation IRCCS Policlinic San Matteo, University of Pavia, Pavia, Italy
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Manuela Nebuloni
4Pathology Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milano, Milano, Italy
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Tommaso Fossali
7Division of Anaesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy
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Riccardo Colombo
7Division of Anaesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy
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Laura Saracino
8Unit of Pneumology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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  • ORCID record for Laura Saracino
Veronica Codullo
9Unit of Rheumatology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
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Massimiliano Gnecchi
10Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Cardiology Unit, University of Pavia, Pavia, Italy
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Paolo Bigini
3Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, Italy
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Fausto Baldanti
2Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
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Daniele Lilleri
2Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
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Federica Meloni
1Research Laboratory of Lung Diseases, Section of Cell Biology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
11University of Pavia and Pneumology Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
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Abstract

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19.

Neutrophils activated with PMA (PMA-Neu), a stimulus known to induce NETs formation, induce both EMT and cell death in the lung epithelial cell line, A549. Notably, NETs isolated from PMA-Neu induce EMT without cell damage. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs. Thus, we tested in an in vitro alveolar model the hypothesis that virus-induced NET may drive EMT. Co-culturing A549 at air-liquid interface with alveolar macrophages, neutrophils and SARS-CoV2, we demonstrated a significant induction of the EMT in A549 together with high concentration of NETs, IL8 and IL1β, best-known inducers of NETosis. Lung tissues of COVID-19 deceased patients showed that epithelial cells are characterized by increased mesenchymal markers. These results show for the first time that NETosis plays a major role in triggering lung fibrosis in COVID-19 patients.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of interest The authors have declared that no conflict of interest exists

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis
Laura Pandolfi, Sara Bozzini, Vanessa Frangipane, Elena Percivalle, Ada De Luigi, Martina Bruna Violatto, Gianluca Lopez, Elisa Gabanti, Luca Carsana, Maura D’Amato, Monica Morosini, Mara De Amici, Manuela Nebuloni, Tommaso Fossali, Riccardo Colombo, Laura Saracino, Veronica Codullo, Massimiliano Gnecchi, Paolo Bigini, Fausto Baldanti, Daniele Lilleri, Federica Meloni
bioRxiv 2020.11.09.374769; doi: https://doi.org/10.1101/2020.11.09.374769
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Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis
Laura Pandolfi, Sara Bozzini, Vanessa Frangipane, Elena Percivalle, Ada De Luigi, Martina Bruna Violatto, Gianluca Lopez, Elisa Gabanti, Luca Carsana, Maura D’Amato, Monica Morosini, Mara De Amici, Manuela Nebuloni, Tommaso Fossali, Riccardo Colombo, Laura Saracino, Veronica Codullo, Massimiliano Gnecchi, Paolo Bigini, Fausto Baldanti, Daniele Lilleri, Federica Meloni
bioRxiv 2020.11.09.374769; doi: https://doi.org/10.1101/2020.11.09.374769

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