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Vol. 1, No. 3, 2009
Issue release date: April 2009
J Innate Immun 2009;1:176–180
(DOI:10.1159/000203699)

Neutrophil Extracellular Traps: A Strategic Tactic to Defeat Pathogens with Potential Consequences for the Host

Medina E.
Infection Immunology Research Group, Department of Microbial Pathogenesis, HZI – Helmholtz Center for Infection Research, Braunschweig, Germany
email Corresponding Author

Abstract

Recent investigations have highlighted new roles for neutrophils in the biology of infection and inflammation. Neutrophils are one of the main players in the innate immune system and actively contribute to host defense by killing pathogens. Added to their ability to eliminate microorganisms by phagocytosis, neutrophils can also kill microbes by capturing them in extracellular structures consisting of granule proteins and DNA called neutrophil extracellular traps (NETs). This review summarizes the recent advancements regarding the structure, production and biological relevance of NETs.


 goto top of outline Key Words

  • Neutrophils
  • Neutrophil extracellular traps
  • Pathogens
  • Antimicrobial mechanisms
  • Mast cell extracellular traps
  • ETosis
  • Reactive oxygen radicals

 goto top of outline Abstract

Recent investigations have highlighted new roles for neutrophils in the biology of infection and inflammation. Neutrophils are one of the main players in the innate immune system and actively contribute to host defense by killing pathogens. Added to their ability to eliminate microorganisms by phagocytosis, neutrophils can also kill microbes by capturing them in extracellular structures consisting of granule proteins and DNA called neutrophil extracellular traps (NETs). This review summarizes the recent advancements regarding the structure, production and biological relevance of NETs.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006;6:173–182.
  2. Hampton MB, Kettle AJ, Winterbourn CC: Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 1998;92:3007–3017.
  3. Segal AW: How neutrophils kill microbes. Annu Rev Immunol 2005;23:197–223.
  4. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–1535.
  5. Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007;5:577–582.
  6. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A : Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007;176:231–241.
  7. Fink SL, Cookson BT: Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005;73:1907–1916.
  8. Wartha F, Henriques-Normark B: ETosis: a novel cell death pathway. Sci Signal 2008;1:pe25.
  9. Urban CF, Reichard U, Brinkmann V, Zychlinsky A: Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006;8:668–676.
  10. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B: An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol 2006;16:401–407.
  11. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V: DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 2006;16:396–400.
  12. Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM, Long RD, Bailey JR, Parnell MJ, Hoe NP, Adams GG, Deleo FR, Musser JM: Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc Natl Acad Sci USA 2005;102:1679–1684.
  13. Udou T, Ichikawa Y: Characteristics of extracellular nuclease production in Staphylococcus aureus. Microbiol Immunol 1979;23:679–684.
  14. Puyet A, Greenberg B, Lacks SA: Genetic and structural characterization of endA. A membrane-bound nuclease required for transformation of Streptococcus pneumoniae. J Mol Biol 1990;213:727–738.
  15. Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, Normark S, Henriques-Normark B: Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol 2007;9:1162–1171.
  16. Lippolis JD, Reinhardt TA, Goff JP, Horst RL: Neutrophil extracellular trap formation by bovine neutrophils is not inhibited by milk. Vet Immunol Immunopathol 2006;113:248–255.
  17. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 1993;177:1367–1383.
  18. Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005;308:1592–1594.
  19. Clark P, Boswell F, Greer IA: The neutrophil and preeclampsia. Semin Reprod Endocrinol 1998;16:57–64.
  20. Zhong XY, Laivuori H, Livingston JC, Ylikorkala O, Sibai BM, Holzgreve W, Hahn S: Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol 2001;184:414–419.
  21. Gupta AK, Hasler P, Holzgreve W, Hahn S: Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia? Semin Immunopathol 2007;29:163–167.
  22. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P: Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007;13:463–469.
  23. von Köckritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, Medina E: Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008;111:3070–3080.
  24. Mekori YA, Metcalfe DD: Mast cells in innate immunity. Immunol Rev 2000;173:131–140.
  25. Marshall JS: Mast-cell responses to pathogens. Nat Rev Immunol 2004;4:787–799.
  26. Malaviya R, Ikeda T, Ross E, Abraham SN: Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 1996;381:77–80.

 goto top of outline Author Contacts

Dr. Eva Medina
Infection Immunology Research Group, Department of Microbial Pathogenesis
Helmholtz Center for Infection Research
Inhoffenstrasse 7, DE–38124 Braunschweig (Germany)
Tel. +49 531 6181 4500, Fax +49 531 6181 4499, E-Mail eva.medina@helmholtz-hzi.de


 goto top of outline Article Information

Received: October 3, 2008
Accepted after revision: October 16, 2008
Published online: February 20, 2009
Number of Print Pages : 5
Number of Figures : 2, Number of Tables : 0, Number of References : 26


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 3, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Recent investigations have highlighted new roles for neutrophils in the biology of infection and inflammation. Neutrophils are one of the main players in the innate immune system and actively contribute to host defense by killing pathogens. Added to their ability to eliminate microorganisms by phagocytosis, neutrophils can also kill microbes by capturing them in extracellular structures consisting of granule proteins and DNA called neutrophil extracellular traps (NETs). This review summarizes the recent advancements regarding the structure, production and biological relevance of NETs.



 goto top of outline Author Contacts

Dr. Eva Medina
Infection Immunology Research Group, Department of Microbial Pathogenesis
Helmholtz Center for Infection Research
Inhoffenstrasse 7, DE–38124 Braunschweig (Germany)
Tel. +49 531 6181 4500, Fax +49 531 6181 4499, E-Mail eva.medina@helmholtz-hzi.de


 goto top of outline Article Information

Received: October 3, 2008
Accepted after revision: October 16, 2008
Published online: February 20, 2009
Number of Print Pages : 5
Number of Figures : 2, Number of Tables : 0, Number of References : 26


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 1, No. 3, Year 2009 (Cover Date: April 2009)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006;6:173–182.
  2. Hampton MB, Kettle AJ, Winterbourn CC: Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 1998;92:3007–3017.
  3. Segal AW: How neutrophils kill microbes. Annu Rev Immunol 2005;23:197–223.
  4. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–1535.
  5. Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007;5:577–582.
  6. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A : Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007;176:231–241.
  7. Fink SL, Cookson BT: Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005;73:1907–1916.
  8. Wartha F, Henriques-Normark B: ETosis: a novel cell death pathway. Sci Signal 2008;1:pe25.
  9. Urban CF, Reichard U, Brinkmann V, Zychlinsky A: Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006;8:668–676.
  10. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B: An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol 2006;16:401–407.
  11. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V: DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 2006;16:396–400.
  12. Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM, Long RD, Bailey JR, Parnell MJ, Hoe NP, Adams GG, Deleo FR, Musser JM: Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc Natl Acad Sci USA 2005;102:1679–1684.
  13. Udou T, Ichikawa Y: Characteristics of extracellular nuclease production in Staphylococcus aureus. Microbiol Immunol 1979;23:679–684.
  14. Puyet A, Greenberg B, Lacks SA: Genetic and structural characterization of endA. A membrane-bound nuclease required for transformation of Streptococcus pneumoniae. J Mol Biol 1990;213:727–738.
  15. Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, Normark S, Henriques-Normark B: Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol 2007;9:1162–1171.
  16. Lippolis JD, Reinhardt TA, Goff JP, Horst RL: Neutrophil extracellular trap formation by bovine neutrophils is not inhibited by milk. Vet Immunol Immunopathol 2006;113:248–255.
  17. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 1993;177:1367–1383.
  18. Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005;308:1592–1594.
  19. Clark P, Boswell F, Greer IA: The neutrophil and preeclampsia. Semin Reprod Endocrinol 1998;16:57–64.
  20. Zhong XY, Laivuori H, Livingston JC, Ylikorkala O, Sibai BM, Holzgreve W, Hahn S: Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol 2001;184:414–419.
  21. Gupta AK, Hasler P, Holzgreve W, Hahn S: Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia? Semin Immunopathol 2007;29:163–167.
  22. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P: Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007;13:463–469.
  23. von Köckritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, Medina E: Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008;111:3070–3080.
  24. Mekori YA, Metcalfe DD: Mast cells in innate immunity. Immunol Rev 2000;173:131–140.
  25. Marshall JS: Mast-cell responses to pathogens. Nat Rev Immunol 2004;4:787–799.
  26. Malaviya R, Ikeda T, Ross E, Abraham SN: Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 1996;381:77–80.