Skip to main content
SpringerLink
Log in

Extracellular Trap by Blood Cells: Clinical Implications

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

Extracellular trap formation (ETosis) by various blood cells has been reported. This trap contains DNA, histones and granular proteins which can elicit an innate immune response by entrapping microorganisms. The trap thus formed has been reported to have an involvement in various pathogenic conditions as well. This review focusses on the trap formation by different blood cells, the immune response associated with trap formation and also its role in various clinical conditions.

METHOD:

An extensive literature survey on ETosis by blood cells from 2003 to 2019 has been done. After going through the literature throughly, in this review we focuses on the trap formation by different blood cell types such as neutrophils, macrophages, eosinophils, basophils, mast cells, plasmacytoid dentritic cells, and monocytes. The mechanism with which it releases trap, the immune response it elicits and ultimately its involvement in various pathogenic conditions are described here. This article extensively covered all the above aspects and finally comprehends in nutshell the various stimuli that are currently known in trigerring the ETosis, its effect and ultimately its role in disease process.

RESULTS:

A clarity about the extracellular trap formation by various blood cells, mechanism of ETosis, role of Etosis in microbial invasion and in various pathogenic situations by various blood cells have been described here.

CONCLUSION:

The current understanding about the process of ETosis and its effects has been extensively described here. Along with lot of favourable outcomes, the process of ETosis will lead to lot of pathogenic situations including thrombosis, tumour metastasis and sepsis. Current understanding about ETosis is limited. Indepth understanding of ETosis may have great therapeutic potential in the diagnosis, guiding of therapy and prognostication in various pathogenic situations including infectious conditions, autoimmune disorders and tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbytnuik LD, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med. 2012;18:1386–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.

    Article  CAS  PubMed  Google Scholar 

  4. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5:e1000639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109:13076–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Boone BA, Orlichenko L, Schapiro NE, Loughran P, Gianfrate GC, Ellis JT, et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 2015;22:326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cedervall J, Zhang Y, Huang H, Zhang L, Femel J, Dimberg A, et al. Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 2015;75:2653–62.

    Article  CAS  PubMed  Google Scholar 

  8. Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol. 2010;185:7413–25.

    Article  CAS  PubMed  Google Scholar 

  9. Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol. 2008;180:1895–902.

    Article  CAS  PubMed  Google Scholar 

  10. Carestia A, Kaufman T, Rivadeneyra L, Landoni VI, Pozner RG, Negrotto S, et al. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J Leukoc Biol. 2016;99:153–62.

    Article  CAS  PubMed  Google Scholar 

  11. Palmer LJ, Cooper PR, Ling MR, Wright HJ, Huissoon A, Chapple IL. Hypochlorous acid regulates neutrophil extracellular trap release in humans. Clin Exp Immunol. 2012;167:261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hamam HJ, Khan MA, Palaniyar N. Histone acetylation promotes neutrophil extracellular trap formation. Biomolecules. 2019;9:E32.

    Article  PubMed  CAS  Google Scholar 

  13. Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 2009;16:1438–44.

    Article  CAS  PubMed  Google Scholar 

  14. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Altmeier S, Toska A, Sparber F, Teijeira A, Halin C, LeibundGut-Landmann S. IL-1 coordinates the neutrophil response to C. albicans in the oral mucosa. PLoS Pathog. 2016;12:e1005882.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Appelgren D, Enocsson H, Skogman BH, Nordberg M, Perander L, Nyman D, et al. Neutrophil extracellular traps (NETs) in the cerebrospinal fluid samples from children and adults with central nervous system infections. Cells. 2019;9:E43.

    Article  PubMed  Google Scholar 

  17. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887–96.

    Article  CAS  PubMed  Google Scholar 

  18. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349:316–320.

    CAS  Google Scholar 

  19. Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10:136–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19:1893–907.

    Article  PubMed  Google Scholar 

  21. Berger-Achituv S, Brinkmann V, Abed UA, Kühn LI, Ben-Ezra J, Elhasid R, et al. A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol. 2013;4:48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123:3446–58.

    Article  CAS  PubMed Central  Google Scholar 

  23. Arelaki S, Arampatzioglou A, Kambas K, Papagoras C, Miltiades P, Angelidou I, et al. Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth. PLoS One. 2016;11:e0154484.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Fadini GP, Menegazzo L, Scattolini V, Gintoli M, Albiero M, Avogaro A. A perspective on NETosis in diabetes and cardiometabolic disorders. Nutr Metab Cardiovasc Dis. 2016;26:1–8.

    Article  CAS  PubMed  Google Scholar 

  25. Menegazzo L, Ciciliot S, Poncina N, Mazzucato M, Persano M, Bonora B, et al. NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol. 2015;52:497–503.

    Article  CAS  PubMed  Google Scholar 

  26. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016;118:1808–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2015;74:1417–24.

    Article  CAS  PubMed  Google Scholar 

  28. Gupta AK, Joshi MB, Philippova M, Erne P, Hasler P, Hahn S, et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett. 2010;584:3193–7.

    Article  CAS  PubMed  Google Scholar 

  29. Bryk AH, Prior SM, Plens K, Konieczynska M, Hohendorff J, Malecki MT, et al. Predictors of neutrophil extracellular traps markers in type 2 diabetes mellitus: associations with a prothrombotic state and hypofibrinolysis. Cardiovasc Diabetol. 2019;18:49.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gupta S, Kaplan MJ. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol. 2016;12:402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim JK, Lee HW, Joo N, Lee HS, Song YR, Kim HJ, et al. Prognostic role of circulating neutrophil extracellular traps levels for long-term mortality in new end-stage renal disease patients. Clin Immunol. 2020;210:108263.

    Article  CAS  PubMed  Google Scholar 

  32. van der Windt DJ, Sud V, Zhang H, Varley PR, Goswami J, Yazdani HO, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018;68:1347–60.

    Article  PubMed  CAS  Google Scholar 

  33. Muñoz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N, et al. Neutrophil extracellular traps initiate gallstone formation. Immunity. 2019;51:443–450.e4.

    Article  PubMed  CAS  Google Scholar 

  34. Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015;21:815–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee YS, Kang SU, Lee MH, Kim HJ, Han CH, Won HR, et al. GnRH impairs diabetic wound healing through enhanced NETosis. Cell Mol Immunol. 2019. https://www.nature.com/articles/s41423-019-0252-y.

  36. Yang C, Chen L, Chen WL, Li N, Chen MJ, Li X, et al. Hydrogen sulfide primes diabetic wound to close through inhibition of NETosis. Mol Cell Endocrinol. 2019;480:74–82.

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Xiao Y, Zhong L, Ye D, Zhang J, Tu Y, et al. Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with β-cell autoimmunity in patients with type 1 diabetes. Diabetes. 2014;63:4239–48.

    Article  CAS  PubMed  Google Scholar 

  38. Yang S, Gu Z, Lu C, Zhang T, Guo X, Xue G, et al. Neutrophil extracellular traps are markers of wound healing impairment in patients with diabetic foot ulcers treated in a multidisciplinary setting. Adv Wound Care (New Rochelle). 2020;9:16–27.

    Article  Google Scholar 

  39. Fadini GP, Menegazzo L, Rigato M, Scattolini V, Poncina N, Bruttocao A, et al. NETosis delays diabetic wound healing in mice and humans. Diabetes. 2016;65:1061–71.

    Article  CAS  PubMed  Google Scholar 

  40. Gautiar EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13:1118–28.

    Article  CAS  Google Scholar 

  41. Farrera C, Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol. 2013;191:2647–56.

    Article  CAS  PubMed  Google Scholar 

  42. Sharma R, O’Sullivan KM, Holdsworth SR, Bardin PG, King PT. Visualizing macrophage extracellular traps using confocal microscopy. J Vis Exp. 2017;2017:e56459.

    Google Scholar 

  43. Mohanan S, Horibata S, McElwee JL, Dannenberg AJ, Coonrod SA. Identification of macrophage extracellular trap-like structures in mammary gland adipose tissue: a preliminary study. Front Immunol. 2013;4:67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Donis-Maturano L, Sánchez-Torres LE, Cerbulo-Vázquez A, Chacón-Salinas R, García-Romo GS, Orozco-Uribe MC, et al. Prolonged exposure to neutrophil extracellular traps can induce mitochondrial damage in macrophages and dendritic cells. Springerplus. 2015;4:161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Wong KW, Jacobs WR. Mycobacterium tuberculosis exploits human interferon γ to stimulate macrophage extracellular trap formation and necrosis. J Infect Dis. 2013;208:109–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu P, Wu X, Liao C, Liu X, Du J, Shi H, et al. Escherichia coli and Candida albicans induced macrophage extracellular trap-like structures with limited microbicidal activity. PLoS One. 2014;9:e90042.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Ueki S, Melo RC, Ghiran I, Spencer LA, Dvorak AM, Weller PF. Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood. 2013;121:2074–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ueki S, Konno Y, Takeda M, Moritoki Y, Hirokawa M, Matsuwaki Y, et al. Eosinophil extracellular trap cell death-derived DNA traps: their presence in secretions and functional attributes. J Allergy Clin Immunol. 2016;137:258–67.

    Article  CAS  PubMed  Google Scholar 

  49. Simon D, Hoesli S, Roth N, Staedler S, Yousefi S, Simon HU. Eosinophil extracellular DNA traps in skin diseases. J Allergy Clin Immunol. 2011;127:194–9.

    Article  CAS  PubMed  Google Scholar 

  50. Choi Y, Le Pham D, Lee DH, Lee SH, Kim SH, Park HS. Biological function of eosinophil extracellular traps in patients with severe eosinophilic asthma. Exp Mol Med. 2018;50:104.

    Article  PubMed Central  CAS  Google Scholar 

  51. Muniz VS, Silva JC, Braga YAV, Melo RCN, Ueki S, Takeda M, et al. Eosinophils release extracellular DNA traps in response to Aspergillus fumigatus. J Allergy Clin Immunol. 2018;141:571–585.e7.

    Article  CAS  PubMed  Google Scholar 

  52. Didichenko SA, Spiegl N, Brunner T, Dahinden CA. IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils. Blood. 2008;112:3949–58.

    Article  CAS  PubMed  Google Scholar 

  53. Schorn C, Janko C, Latzko M, Chaurio R, Schett G, Herrmann M. Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells. Front Immunol. 2012;3:277.

    PubMed  PubMed Central  Google Scholar 

  54. Morshed M, Hlushchuk R, Simon D, Walls AF, Obata-Ninomiya K, Karasuyama H, et al. NADPH oxidase-independent formation of extracellular DNA traps by basophils. J Immunol. 2014;192:5314–23.

    Article  CAS  PubMed  Google Scholar 

  55. Yousefi S, Morshed M, Amini P, Stojkov D, Simon D, von Gunten S, et al. Basophils exhibit antibacterial activity through extracellular trap formation. Allergy. 2015;70:1184–8.

    Article  CAS  PubMed  Google Scholar 

  56. von Köckritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood. 2008;111:3070–80.

    Article  CAS  Google Scholar 

  57. Di Nardo A, Vitiello A, Gallo RL. Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol. 2003;170:2274–8.

    Article  PubMed  Google Scholar 

  58. Naqvi N, Ahuja K, Selvapandiyan A, Dey R, Nakhasi H, Puri N. Role of mast cells in clearance of Leishmania through extracellular trap formation. Sci Rep. 2017;7:13240.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lopes JP, Stylianou M, Nilsson G, Urban CF. Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells. Sci Rep. 2015;5:12287.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Clark M, Kim J, Etesami N, Shimamoto J, Whalen RV, Martin G, et al. Group A Streptococcus prevents mast cell degranulation to promote extracellular trap formation. Front Immunol. 2018;9:327.

    Article  CAS  Google Scholar 

  61. Campillo-Navarro M, Leyva-Paredes K, Donis-Maturano L, Rodríguez-López GM, Soria-Castro R, García-Pérez BE, et al. Mycobacterium tuberculosis catalase inhibits the formation of mast cell extracellular traps. Front Immunol. 2018;9:327.

    Article  CAS  Google Scholar 

  62. Pertiwi KR, de Boer OJ, Mackaaij C, Pabittei DR, de Winter RJ, Li X, et al. Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis. J Pathol. 2019;247:505–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Skrzeczynska-Moncznik J, Wlodarczyk A, Banas M, Kwitniewski M, Zabieglo K, Kapinska-Mrowiecka M, et al. DNA structures decorated with cathepsin G/secretory leukocyte proteinase inhibitor stimulate IFNI production by plasmacytoid dendritic cells. Am J Clin Exp Immunol. 2013;2:186–94.

    PubMed  PubMed Central  Google Scholar 

  64. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Loures FV, Röhm M, Lee CK, Santos E, Wang JP, Specht CA, et al. Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by Dectin-2 and results in formation of extracellular traps. PLoS Pathog. 2015;11:e1004643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Landsman L, Varol C, Jung S. Distinct differentiation potential of blood monocyte subsets in the lung. J Immunol. 2007;178:2000–7.

    Article  CAS  PubMed  Google Scholar 

  67. Granger V, Faille D, Marani V, Noël B, Gallais Y, Szely N, et al. Human blood monocytes are able to form extracellular traps. J Leukoc Biol. 2017;102:775–81.

    Article  CAS  PubMed  Google Scholar 

  68. Muñoz-Caro T, Silva LM, Ritter C, Taubert A, Hermosilla C. Besnoitia besnoiti tachyzoites induce monocyte extracellular trap formation. Parasitol Res. 2014;113:4189–97.

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

The authors are grateful for the support and infrastructure provided by the Centre for Nanoscience and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, India

Author information

Author notes

  1. R. J. Nija and S. Sanju equally contributed.

Authors and Affiliations

  1. Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, 682041, India

    R. J. Nija, S. Sanju & Ullas Mony

  2. Department of Clinical Hematology and Stem Cell Transplant, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, 682041, India

    Neeraj Sidharthan

Authors
  1. R. J. Nija
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Sanju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neeraj Sidharthan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ullas Mony
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Neeraj Sidharthan or Ullas Mony.

Ethics declarations

Conflict of interest

All authors declare that there is no conflict of interest

Ethical statement

There are no animal experiments carried out for this article

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nija, R.J., Sanju, S., Sidharthan, N. et al. Extracellular Trap by Blood Cells: Clinical Implications. Tissue Eng Regen Med 17, 141–153 (2020). https://doi.org/10.1007/s13770-020-00241-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-020-00241-z

Keywords

Search

Navigation