PT  - JOURNAL ARTICLE
AU  - Laura Pandolfi
AU  - Sara Bozzini
AU  - Vanessa Frangipane
AU  - Elena Percivalle
AU  - Ada De Luigi
AU  - Martina Bruna Violatto
AU  - Gianluca Lopez
AU  - Elisa Gabanti
AU  - Luca Carsana
AU  - Maura D’Amato
AU  - Monica Morosini
AU  - Mara De Amici
AU  - Manuela Nebuloni
AU  - Tommaso Fossali
AU  - Riccardo Colombo
AU  - Laura Saracino
AU  - Veronica Codullo
AU  - Massimiliano Gnecchi
AU  - Paolo Bigini
AU  - Fausto Baldanti
AU  - Daniele Lilleri
AU  - Federica Meloni
TI  - Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis
AID  - 10.1101/2020.11.09.374769
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.09.374769
4099  - http://biorxiv.org/content/early/2020/11/09/2020.11.09.374769.short
4100  - http://biorxiv.org/content/early/2020/11/09/2020.11.09.374769.full
AB  - 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 StatementThe authors have declared no competing interest.