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Cited by 1,486Neutrophil, Myeloperoxidase and Oxidative MechanismsCOVID-19 Clinical Research StudiesInflammation biomarkers and pathways

The DOI matches its Crossref record; 88 of the 88 references it cites were found in a registry or an index.

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

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Barnes, Betsy J., Adrover, Jose M., Baxter-Stoltzfus, Amelia, Borczuk, Alain, Cools-Lartigue, Jonathan, Crawford, James M., Daßler-Plenker, Juliane, Guerci, Philippe, Huynh, Caroline, Knight, Jason S., Loda, Massimo, Looney, Mark R., McAllister, Florencia, Rayes, Roni, Renaud, Stephane, Rousseau, Simon, Salvatore, Steven, Schwartz, Robert E., Spicer, Jonathan D., Yost, Christian C., Weber, Andrew, Zuo, Yu, Egeblad, Mikala·2020·Journal of Experimental Medicine
DOI 10.1084/jem.20200652PMC PMC7161085
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Abstract

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

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Figure 1. Neutrophils in an autopsy specimen from the lungs of a patient who succumbed from COVID-19. (A) Extensive neutrophil infiltration in pulmonary capillaries, with acute capillaritis with fibrin deposition, and extravasation into the alveolar space. An image was chosen to emphasize the capillary lesions. (B) Neutrophilic mucositis of the trachea. The entire airway was affected (images by A. Borczuk, Weill Cornell Medical Center). Both specimens originate from a 64-yr-old male of Hispanic decent with diabetes, end-stage renal disease on hemodialysis, heart failure, and hepatitis C on ledipasvir/sofosbuvir therapy. He declined medical intervention, was therefore not intubated, and died in the emergency room 5 h after presentation, shortly after developing fever. There was no evidence of sepsis in this patient clinically, premortem cultures were negative, and the autopsy was performed within 5 h of death. Similar neutrophil distribution, but with less extensive infiltration, was observed in the two additional autopsies analyzed to date. These other two cases had longer duration of symptoms. Scale bars: 50 µm.
Figure 1. Neutrophils in an autopsy specimen from the lungs of a patient who succumbed from COVID-19. (A) Extensive neutrophil infiltration in pulmonary capillaries, with acute capillaritis with fibrin deposition, and extravasation into the alveolar space. An image was chosen to emphasize the capillary lesions. (B) Neutrophilic mucositis of the trachea. The entire airway was affected (images by A. Borczuk, Weill Cornell Medical Center). Both specimens originate from a 64-yr-old male of Hispanic decent with diabetes, end-stage renal disease on hemodialysis, heart failure, and hepatitis C on ledipasvir/sofosbuvir therapy. He declined medical intervention, was therefore not intubated, and died in the emergency room 5 h after presentation, shortly after developing fever. There was no evidence of sepsis in this patient clinically, premortem cultures were negative, and the autopsy was performed within 5 h of death. Similar neutrophil distribution, but with less extensive infiltration, was observed in the two additional autopsies analyzed to date. These other two cases had longer duration of symptoms. Scale bars: 50 µm.CC BY-NC-SA · PubMed Central
Figure 2. Neutrophils forming NETs in cell culture. Note the expelled DNA strings (arrows). Scanning electron microscopy of neutrophils 3 h after plating and coculturing with 4T1 breast cancer cells. Scale bar: 25 µm.
Figure 2. Neutrophils forming NETs in cell culture. Note the expelled DNA strings (arrows). Scanning electron microscopy of neutrophils 3 h after plating and coculturing with 4T1 breast cancer cells. Scale bar: 25 µm.CC BY-NC-SA · PubMed Central
Figure 3. Excess NET formation can drive a variety of severe pathologies. In the lungs, NETs drive the accumulation of mucus in CF patients’ airways. NETs also drive ARDS after a variety of inducers, including influenza. In the vascular system, NETs drive atherosclerosis and aortic aneurysms, as well as thrombosis (particularly microthrombosis), with devastating effects on organ function.
Figure 3. Excess NET formation can drive a variety of severe pathologies. In the lungs, NETs drive the accumulation of mucus in CF patients’ airways. NETs also drive ARDS after a variety of inducers, including influenza. In the vascular system, NETs drive atherosclerosis and aortic aneurysms, as well as thrombosis (particularly microthrombosis), with devastating effects on organ function.CC BY-NC-SA · PubMed Central
Figure 4. Approaches to targeting NETs. NETs can be targeted by existing drugs through several means. NE, PAD4, and gasdermin D inhibitors will prevent NET formation. DNase has been used safely to digest NETs in the mucous secretions of the airways of CF patients. Colchicine inhibits neutrophil migration and infiltration into sites of inflammation. IL1β blockers will prevent an inflammatory loop between NETs and IL1β. Of these approaches, trials to treat COVID-19 with colchicine and anakinra are already ongoing or being launched (ClinicalTrials.gov identifiers: NCT04324021, NCT04330638, NCT02735707, NCT04326790, NCT04328480, NCT04322565, NCT04322682).
Figure 4. Approaches to targeting NETs. NETs can be targeted by existing drugs through several means. NE, PAD4, and gasdermin D inhibitors will prevent NET formation. DNase has been used safely to digest NETs in the mucous secretions of the airways of CF patients. Colchicine inhibits neutrophil migration and infiltration into sites of inflammation. IL1β blockers will prevent an inflammatory loop between NETs and IL1β. Of these approaches, trials to treat COVID-19 with colchicine and anakinra are already ongoing or being launched (ClinicalTrials.gov identifiers: NCT04324021, NCT04330638, NCT02735707, NCT04326790, NCT04328480, NCT04322565, NCT04322682).CC BY-NC-SA · PubMed Central

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Authors
Barnes, B. J., Adrover, J. M., Baxter-Stoltzfus, A., Borczuk, A., Cools-Lartigue, J., Crawford, J. M., Daßler-Plenker, J., Guerci, P., Huynh, C., Knight, J. S., Loda, M., Looney, M. R., McAllister, F., Rayes, R., Renaud, S., Rousseau, S., Salvatore, S., Schwartz, R. E., Spicer, J. D., Yost, C. C., Weber, A., Zuo, Y., & Egeblad, M.
Affiliations
  • Feinstein Institute for Medical Research (US)
  • Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 2
  • Weill Cornell Medicine (US)
  • Division of Thoracic and Upper GI Surgery, Department of Surgery, Montreal, Canada 4
  • Hofstra University (US)
  • Centre Hospitalier Régional et Universitaire de Nancy (FR)
  • McGill University (CA)
  • University of Michigan (US)
  • University of California, San Francisco (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Centre Hospitalier Universitaire de Nancy, Nancy, France 6
  • Research Institute of the McGill University Health Centre (CA)
  • University of Utah (US)
  • Northwell Health (US)
  • Cold Spring Harbor Laboratory (US)
Corresponding author
  • Barnes, Betsy J.
  • Egeblad, Mikala
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2020-04-16
Volume
217
Issue
6
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20200652
PMC
PMC7161085
OpenAlex
W3016393661
Cited by
1,486
References
84
Citations by year
2026: 34 · 2025: 70 · 2024: 124 · 2023: 150 · 2022: 288 · 2021: 438 · 2020: 378
FWCI
110.17
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • eScholarship@McGill (McGill) (submittedVersion)
Funders
  • National Institutes of Health (5p30ca045508-35)
  • National Heart, Lung, and Blood Institute (R01HL130324, R01HL134846)
  • National Cancer Institute (P30-CA045508)
  • National Institute of Allergy and Infectious Diseases (R01AI125445)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121072)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR076242)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD093826)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
COVID-19 pandemic, neutrophil extracellular traps, neutrophils, acute respiratory distress syndrome, cytokine storm, lung infiltration, organ damage, thrombosis, airway mucus secretion, targeted drug delivery, autopsy findings
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, Humans, Lung Diseases, Neutrophils, Pneumonia, Viral, Cytokines, Coronavirus Infections, Pandemics, Extracellular Traps

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