To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Sebastian Boeltz¹, Poorya Amini², Hans-Joachim Anders³, Felipe Andrade⁴, Rostyslav Bilyy⁵, Simon Chatfield⁶, Iwona Cichon⁷, Danielle M Clancy⁸, Jyaysi Desai³, Tetiana Dumych⁵, Nishant Dwivedi^{9

10}, Rachael Ann Gordon¹¹, Jonas Hahn¹, Andrés Hidalgo^{12

13}, Markus H Hoffmann¹⁴, Mariana J Kaplan¹⁵, Jason S Knight¹⁶, Elzbieta Kolaczkowska⁷, Paul Kubes¹⁷, Moritz Leppkes¹⁸, Angelo A Manfredi¹⁹, Seamus J Martin²⁰, Christian Maueröder^{1

8}, Norma Maugeri¹⁹, Ioannis Mitroulis^{21

22}, Luis E Munoz¹, Daigo Nakazawa³, Indira Neeli²³, Victor Nizet^{24

25}, Elmar Pieterse²⁶, Marko Z Radic²³, Christiane Reinwald¹, Konstantinos Ritis^{21

22}, Patrizia Rovere-Querini¹⁹, Michal Santocki⁷, Christine Schauer¹, Georg Schett¹, Mark Jay Shlomchik¹¹, Hans-Uwe Simon^{2

27}, Panagiotis Skendros^{21

22}, Darko Stojkov², Peter Vandenabeele^{8

28

29}, Tom Vanden Berghe^{8

28

30}, Johan van der Vlag²⁶, Ljubomir Vitkov^{31

32}, Maren von Köckritz-Blickwede³³, Shida Yousefi², Alexander Zarbock³⁴, Martin Herrmann¹

Affiliations

¹ Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.
² Institute of Pharmacology, University of Bern, Bern, Switzerland.
³ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
⁴ Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
⁶ Inflammation Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
⁷ Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland.
⁸ VIB-UGent Center for Inflammation Research, University of Gent, Gent, Belgium.
⁹ Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Harvard Medical School, Boston, MA, USA.
¹¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹² Department of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spain.
¹³ Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany.
¹⁴ Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany. markus.hoffmann@uk-erlangen.de.
¹⁵ Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, USA.
¹⁶ Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Snyder institute of Chronic Diseases, University of Calgary, Calgary, Canada.
¹⁸ Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
¹⁹ Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy.
²⁰ Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
²¹ Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
²² First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
²³ Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
²⁴ UC San Diego School of Medicine, La Jolla, CA, USA.
²⁵ Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA.
²⁶ Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁷ Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.
²⁸ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
²⁹ Methusalem platform, Ghent University, Ghent, Belgium.
³⁰ Laboratory of Pathophysiology, Faculty of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
³¹ Department of Biosciences, Vascular & Exercise Biology Unit, University of Salzburg, Salzburg, Austria.
³² Periodontology and Preventive Dentistry, Saarland University, Homburg, Germany.
³³ Department of Physiological Chemistry & Research Center for Emerging Infections and Zoonosis (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
³⁴ University of Münster, Department of Anesthesiology, Intensive Care and Pain Medicine, Münster, Germany.

PMID: 30622307
PMCID: PMC6370810
DOI: 10.1038/s41418-018-0261-x

Review

To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Sebastian Boeltz et al. Cell Death Differ. 2019 Mar.

. 2019 Mar;26(3):395-408.

doi: 10.1038/s41418-018-0261-x. Epub 2019 Jan 8.

Authors

Affiliations

¹ Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.
² Institute of Pharmacology, University of Bern, Bern, Switzerland.
³ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
⁴ Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
⁶ Inflammation Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
⁷ Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland.
⁸ VIB-UGent Center for Inflammation Research, University of Gent, Gent, Belgium.
⁹ Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Harvard Medical School, Boston, MA, USA.
¹¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹² Department of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spain.
¹³ Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany.
¹⁴ Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany. markus.hoffmann@uk-erlangen.de.
¹⁵ Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, USA.
¹⁶ Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Snyder institute of Chronic Diseases, University of Calgary, Calgary, Canada.
¹⁸ Department of Medicine 1 - Gastroenterology, Pulmonology and Endocrinology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
¹⁹ Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy.
²⁰ Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
²¹ Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
²² First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
²³ Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
²⁴ UC San Diego School of Medicine, La Jolla, CA, USA.
²⁵ Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, USA.
²⁶ Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁷ Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.
²⁸ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
²⁹ Methusalem platform, Ghent University, Ghent, Belgium.
³⁰ Laboratory of Pathophysiology, Faculty of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
³¹ Department of Biosciences, Vascular & Exercise Biology Unit, University of Salzburg, Salzburg, Austria.
³² Periodontology and Preventive Dentistry, Saarland University, Homburg, Germany.
³³ Department of Physiological Chemistry & Research Center for Emerging Infections and Zoonosis (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
³⁴ University of Münster, Department of Anesthesiology, Intensive Care and Pain Medicine, Münster, Germany.

PMID: 30622307
PMCID: PMC6370810
DOI: 10.1038/s41418-018-0261-x

Abstract

Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.

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Conflict of interest statement

FA is an inventor on issued patent no. 8,975,033 held by The Johns Hopkins University that covers “Human autoantibodies specific for PAD3 which are cross-reactive with PAD4 and their use in the diagnosis and treatment of rheumatoid arthritis and related diseases” and serves as a consultant for Bristol-Myers Squibb. The other authors declare no competing interests.

Figures

**Fig. 1**
Number of publications including the term “neutrophil extra-cellular trap” per year (according to PubMed)

**Fig. 2**
Current areas of consensus and controversy about neutrophil extracellular traps (NETs)

See this image and copyright information in PMC

References

1. Kavenoff R, Zimm BH. Chromosome-sized DNA molecules from Drosophila. Chromosoma. 1973;41:1–27. doi: 10.1007/BF00284071. - DOI - PubMed
1. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5. doi: 10.1126/science.1092385. - DOI - PubMed
1. Kenny EF, Herzig A, Kruger R, Muth A, Mondal S, Thompson PR, et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017;6. - PMC - PubMed
1. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19. doi: 10.1126/scitranslmed.3001180. - DOI - PMC - PubMed
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To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Affiliations

To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources