TY - JOUR
T1 - Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition
T2 - Implications in Post-COVID-19 Fibrosis
AU - Pandolfi, Laura
AU - Bozzini, Sara
AU - Frangipane, Vanessa
AU - Percivalle, Elena
AU - De Luigi, Ada
AU - Violatto, Martina Bruna
AU - Lopez, Gianluca
AU - Gabanti, Elisa
AU - Carsana, Luca
AU - D’Amato, Maura
AU - Morosini, Monica
AU - De Amici, Mara
AU - Nebuloni, Manuela
AU - Fossali, Tommaso
AU - Colombo, Riccardo
AU - Saracino, Laura
AU - Codullo, Veronica
AU - Gnecchi, Massimiliano
AU - Bigini, Paolo
AU - Baldanti, Fausto
AU - Lilleri, Daniele
AU - Meloni, Federica
N1 - Funding Information:
Monti Manuela PhD (Laboratory of Biotechnology, Center of Regenerative Medicine Research, IRCCS San Matteo Foundation, Pavia, Italy) for the use of confocal microscopy. Testa Giorgia (Pediatrics Clinic, IRCCS Policlinico S. Matteo Foundation, Pavia, University of Pavia Italy) for the analysis of IL1?.
Funding Information:
Fondazione Cariplo (COVIM project); Ministry of Health funds to IRCCS Foundation Policlinico San Matteo Grant (RC) and Ministry of Health funds COVID-2020-12371760. The funders had no role in study design, data collection and analysis, or preparation of the manuscript.
Publisher Copyright:
© Copyright © 2021 Pandolfi, Bozzini, Frangipane, Percivalle, De Luigi, Violatto, Lopez, Gabanti, Carsana, D’Amato, Morosini, De Amici, Nebuloni, Fossali, Colombo, Saracino, Codullo, Gnecchi, Bigini, Baldanti, Lilleri and Meloni.
PY - 2021/6/14
Y1 - 2021/6/14
N2 - 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. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.
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. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.
KW - COVID-19
KW - epithelial-mesenchymal transition
KW - lung fibrosis
KW - NETosis
KW - SARS-CoV2
UR - http://www.scopus.com/inward/record.url?scp=85108980269&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108980269&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.663303
DO - 10.3389/fimmu.2021.663303
M3 - Article
AN - SCOPUS:85108980269
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 663303
ER -