NETs: a new strategy for using old weapons
Abstract
As key players in the host innate immune response, neutrophils are recruited to sites of infection and constitute the first line of defense. They employ three strategies to eliminate invading microbes: microbial uptake, the secretion of antimicrobials, and the recently described release of Neutrophil Extracellular Traps (NETs). Composed of decondensed chromatin and antimicrobial proteins, NETs bind and kill a variety of microbes including bacteria, fungi, and parasites. In addition to using a repertoire of known antimicrobials, NETs incorporate histones into the antimicrobial arsenal. Furthermore, NETs may contribute to microbial containment by forming a physical barrier and a scaffold, to enhance antimicrobial synergy while minimizing damage to host tissues. Their role in innate immunity is only now being uncovered.
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Neutrophils can eliminate organisms residing in the extracellular environment through the deployment of neutrophil extracellular traps (NETs).
“More recent evidence indicates that neutrophils can also eliminate organisms residing in the extracellular environment through the deployment of neutrophil extracellular traps (NETs).”
From Immunology of Wound Healing (2018) · cites this paper as [41]
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Neutrophil recruitment and function in health and inflammation
Kolaczkowska, E., & Kubes, P. (2013) · Nature Reviews Immunology · doi:10.1038/nri3399 · Cited by 5,472 · see citing works
Atherosclerosis: current pathogenesis and therapeutic options
Weber, C., & Noels, H. (2011) · Nature Medicine · doi:10.1038/nm.2538 · Cited by 2,203 · see citing works
“Furthermore, neutrophils activated through TLRs, Fc receptors or cytokine receptors can release nuclear content (DNA fibers, chromatin) that forms a scaffold containing antimicrobial proteins, such as LL-37, termed neutrophil extracellular traps (NETs”
BackgroundNeutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps
Papayannopoulos, V., Metzler, K. D., Hakkim, A., & Zychlinsky, A. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201006052 · Cited by 2,103 · see citing works
“NETs are implicated in immune defense, sepsis, and autoimmunity (Clark et al., 2007; Kessenbrock et al., 2009; Papayannopoulos and Zychlinsky, 2009; Hakkim et al., 2010).”
BackgroundSelf-citationNeutrophil Function: From Mechanisms to Disease
Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D., & Zychlinsky, A. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074942 · Cited by 1,695 · see citing works
Self-citationPathogenicity and virulence of Staphylococcus aureus
Cheung, G. Y. C., Bae, J. S., & Otto, M. J. (2021) · Virulence · doi:10.1080/21505594.2021.1878688 · Cited by 1,456 · see citing works
“(“NETosis”) [136], is also believed to contribute to host defense against S.”
BackgroundThe multifaceted functions of neutrophils
Mayadas, T. N., Cullere, X., & Lowell, C. A. (2014) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-164023 · Cited by 1,356 · see citing works
“Moreover, histones themselves have significant antimicrobial activity (124).”
Villanueva, E. C., Yalavarthi, S., Berthier, C. C., Hodgin, J. B., Khandpur, R., Lin, A. M., Rubin, C. J., Zhao, W., Olsen, S. H., Klinker, M. W., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100450 · Cited by 1,246 · see citing works
Phagocyte partnership during the onset and resolution of inflammation
Soehnlein, O., & Lindbom, L. (2010) · Nature Reviews Immunology · doi:10.1038/nri2779 · Cited by 1,054 · see citing works
Falanga, V., Isseroff, R. R., Soulika, A. M., Romanelli, M., Margolis, D. J., Kapp, S., Granick, M. S., & Harding, K. G. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00377-3 · Cited by 1,102 · see citing works
Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines
Schauer, C., Janko, C., Munoz, L. E., Zhao, Y., Kienhöfer, D., Frey, B., Lell, M., Manger, B., Rech, J., Naschberger, E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3547 · Cited by 998 · see citing works
SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology
Veras, F. P., Pontelli, M. C., Silva, C. M. S., Toller-Kawahisa, J. E., de Lima, M., Nascimento, D. C., Schneider, A. H., Caetité, D. B., Tavares, L., Paiva, I. M., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201129 · Cited by 924 · see citing works
Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases
Korkmaz, B., Horwitz, M. S., Jenne, D. E., & Gauthier, F. (2010) · Pharmacological Reviews · doi:10.1124/pr.110.002733 · Cited by 873 · see citing works
Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation
Hakkim, A., Fuchs, T. A., Martinez, N. E., Hess, S., Prinz, H., Zychlinsky, A., & Waldmann, H. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.496 · Cited by 793 · see citing works
Self-citationMetzler, K. D., Fuchs, T. A., Nauseef, W. M., Reumaux, D., Roesler, J., Schulze, I., Wahn, V., Papayannopoulos, V., & Zychlinsky, A. (2010) · Blood · doi:10.1182/blood-2010-06-290171 · Cited by 775 · see citing works
Self-citationIntravascular Neutrophil Extracellular Traps Capture Bacteria from the Bloodstream during Sepsis
McDonald, B., Urrutia, R., Yipp, B. G., Jenne, C. N., & Kubes, P. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.06.011 · Cited by 772 · see citing works
“Interestingly, neutrophils are endowed with effector mechanisms termed neutrophil extracellular traps (NETs, large webs of decondensed chromatin coated with granule proteins) that are expelled from activated neutrophils that can capture and kill microbes in the extracellular space (Brinkmann et al., 2004; Papayannopou…”
BackgroundInfluentialNeutrophil Extracellular Traps Mediate a Host Defense Response to Human Immunodeficiency Virus-1
Saitoh, T., Komano, J. A., Saitoh, Y., Misawa, T., Takahama, M., Kozaki, T., Uehata, T., Iwasaki, H., Omori, H., Yamaoka, S., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.05.015 · Cited by 731 · see citing works
The role of neutrophils during intestinal inflammation
Fournier, B., & Parkos, C. A. (2012) · Mucosal Immunology · doi:10.1038/mi.2012.24 · Cited by 677 · see citing works
Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns
Schaefer, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.619304 · Cited by 618 · see citing works
“In bacterial infections, histones are generally released either by dying neutrophils, especially during the formation process of the so-called neutrophil extracellular traps (60), or by dying tubular epithelial cells (58).”
BackgroundEllis, S., Lin, E. J., & Tartar, D. (2018) · Current Dermatology Reports · doi:10.1007/s13671-018-0234-9 · Cited by 625 · see citing works
Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality
Remijsen, Q., Kuijpers, T. W., Wirawan, E., Lippens, S., Vandenabeele, P., & Berghe, T. V. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.1 · Cited by 612 · see citing works
“However, only very few NETs, if any, are generated by HL-60 cells, regardless of their differentiation state.(30,41,50) This may be explained by defects in their ability to induce autophagy.”
Solana, R., Tarazona, R., Gayoso, I., Lesur, O., Dupuis, G., & Fulop, T. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.008 · Cited by 567 · see citing works
“[11] Papayannopoulos V, Zychlinsky A.”
BackgroundInfluentialUnderstanding the mechanisms of faecal microbiota transplantation
Khoruts, A., & Sadowsky, M. J. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.98 · Cited by 563 · see citing works
Gupta, A. K., Joshi, M. B., Philippova, M., Erné, P., Hasler, P., Hahn, S., & Resink, T. J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.06.006 · Cited by 538 · see citing works
“A unique aspect of polymorphonuclear neutrophil (PMN) antimicrobial defence is their ability to release chromatin and granular proteins to form an extracellular fibrillar matrix termed neutrophil extracellular traps (NETs) [1,2].”
BackgroundMultiple Roles for Neutrophils in Atherosclerosis
Soehnlein, O. (2012) · Circulation Research · doi:10.1161/circresaha.111.257535 · Cited by 498 · see citing works
Selders, G. S., Fetz, A. E., Radic, M. Z., & Bowlin, G. L. (2017) · Regenerative Biomaterials · doi:10.1093/rb/rbw041 · Cited by 538 · see citing works
“Although protease dispersal via NETs is implicated in further tissue destruction, the role of proteases is not limited to cleaving bacterial factors, as they are potent antimicrobial agents that can actually end up neutralizing their own effects [25, 58].”
BackgroundInfluentialMacrophage Clearance of Neutrophil Extracellular Traps Is a Silent Process
Farrera, C., & Fadeel, B. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300436 · Cited by 445 · see citing works
“NETs are believed to be an effective defense system against infection, as the entrapment of pathogens in NETs may aid in the local confinement of the infection, whereas the granule-derived enzymes facilitate in the extracellular killing of the “netted” pathogens (4).”
BackgroundNeutrophils: Cinderella of innate immune system
Kumar, V., & Sharma, A. (2010) · International Immunopharmacology · doi:10.1016/j.intimp.2010.08.012 · Cited by 442 · see citing works
“of infection along with decreasing inflammation by releasing antiinflammatory lipoxins and lowering pathogen load [25].”
BackgroundHistones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4
Allam, R., Scherbaum, C. R., Darisipudi, M. N., Mulay, S. R., Hägele, H., Lichtnekert, J., Hagemann, J. H., Rupanagudi, K. V., Ryu, M., Schwarzenberger, C., et al. (2012) · Journal of the American Society of Nephrology · doi:10.1681/asn.2011111077 · Cited by 431 · see citing works
Neutrophils in Cancer: Two Sides of the Same Coin
Uribe‐Querol, E., & Rosales, C. (2015) · Journal of Immunology Research · doi:10.1155/2015/983698 · Cited by 425 · see citing works
“Bacterial products such as lipo polysaccharide (LPS), formyl-methionyl-leucyl-phenylalanine (fMLF), and also phorbol esters such as phorbol myristate acetate (PMA) are efficient NET inducers [200].”
BackgroundNeutrophil recruitment to the brain in mouse and human ischemic stroke
Perez-de-Puig, I., Miró-Mur, F., Ferrer-Ferrer, M., Gelpi, E., Pedragosa, J., Justicia, C., Urra, X., Chamorro, A., & Planas, A. M. (2015) · Acta Neuropathologica · doi:10.1007/s00401-014-1381-0 · Cited by 420 · see citing works
“Prior to releasing NETs, neutrophil enzymes access the cell nucleus and promote chromatin decondensation [42] involving histone modifications.”
BackgroundMethodPathogenesis of Proteus mirabilis Infection
Armbruster, C. E., Mobley, H. L. T., & Pearson, M. M. (2018) · EcoSal Plus · doi:10.1128/ecosalplus.esp-0009-2017 · Cited by 414 · see citing works
Activation of PAD4 in NET formation
Rohrbach, A. S., Slade, D. J., Thompson, P. R., & Mowen, K. A. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00360 · Cited by 404 · see citing works
“These structures represent a novel method for pathogen killing, independent of both degranulation and phagocytosis, and have been shown to effectively kill a variety of pathogens, including bacteria, fungi, and protozoa (Papayannopoulos and Zychlinsky, 2009; Remijsen et al., 2011a).”
BackgroundMethodNeutrophils in innate host defense against Staphylococcus aureus infections
Rigby, K. M., & DeLeo, F. R. (2012) · Seminars in Immunopathology · doi:10.1007/s00281-011-0295-3 · Cited by 400 · see citing works
“Extrusion of such structures by neutrophils is predicted to limit microbial spread and dissemination, while enhancing effective concentrations of extruded microbicidal agents, thereby promoting synergistic killing of attached microorganisms [222].”
BackgroundMitroulis, I., Kambas, K., Chrysanthopoulou, A., Skendros, P., Apostolidou, E., Kourtzelis, I., Drosos, G. I., Boumpas, D. T., & Ritis, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029318 · Cited by 378 · see citing works
“NETs are extracellular fibrous structures composed of chromatin and granule constituents of neutrophils [22].”
BackgroundNeutrophils at the crossroads of innate and adaptive immunity
Rosales, C. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.4mir0220-574rr · Cited by 372 · see citing works
Neutrophil clearance: when the party is over, clean-up begins
Bratton, D. L., & Henson, P. M. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.04.009 · Cited by 350 · see citing works
“The process involves NADPH oxidase-dependent dissolution of the nucleus and intracellular membranes and rupture of the plasma membrane [20].”
BackgroundBiofilms in Periprosthetic Orthopedic Infections
McConoughey, S. J., Howlin, R. P., Granger, J. F., Manring, M. M., Calhoun, J. H., Shirtliff, M. E., Kathju, S., & Stoodley, P. (2014) · Future Microbiology · doi:10.2217/fmb.14.64 · Cited by 343 · see citing works
The role of extracellular histone in organ injury
Silk, E., Zhao, H., Weng, H., & Ma, D. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.52 · Cited by 331 · see citing works
“and histones, NETs have protective and pathogenic functions.(30,31) When released from neutrophils during infec-”
BackgroundT Lymphocyte Priming by Neutrophil Extracellular Traps Links Innate and Adaptive Immune Responses
Tillack, K., Breiden, P., Martinꝉ, R., & Sospedra, M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103414 · Cited by 329 · see citing works
“The composition of NETs, being fibers of chromatin decorated with antimicrobial proteins, turns them into optimal structures to perform this task (16).”
BackgroundPlatelets: versatile effector cells in hemostasis, inflammation, and the immune continuum
Vieira‐de‐Abreu, A., Campbell, R. A., Weyrich, A. S., & Zimmerman, G. A. (2011) · Seminars in Immunopathology · doi:10.1007/s00281-011-0286-4 · Cited by 323 · see citing works
“formation of NETs is a newly recognized mechanism of extracellular bacterial capture and killing [47, 58, 69, 73] that may be impaired in human infections and immunodeficiencies [72].”
BackgroundMolecular mechanisms regulating NETosis in infection and disease
Branzk, N., & Papayannopoulos, V. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0384-6 · Cited by 319 · see citing works
Self-citationCauwe, B., & Opdenakker, G. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.501783 · Cited by 296 · see citing works
Najmeh, S., Cools‐Lartigue, J., Rayes, R. F., Gowing, S. D., Vourtzoumis, P., Bourdeau, F., Giannias, B., Bérubé, J., Rousseau, S., Ferri, L. E., et al. (2017) · International Journal of Cancer · doi:10.1002/ijc.30635 · Cited by 298 · see citing works
“Neutrophils were found, under specific stimuli, to have the unique ability to form Neutrophil Extracellular Traps (NETs).(19,20) This process, also termed NETosis results in local formation of web-like projections of extracellular decondensed chromatin DNA decorated by numerous neutrophilderived histones and peptides.”
BackgroundNETosis markers: Quest for specific, objective, and quantitative markers
Masuda, S., Nakazawa, D., Shida, H., Miyoshi, A., Kusunoki, Y., Tomaru, U., & Ishizu, A. (2016) · Clinica Chimica Acta · doi:10.1016/j.cca.2016.05.029 · Cited by 289 · see citing works
“Currently, it is considered that NET appears to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents derived from neutrophils [3].”
BackgroundProgrammed cell death and its role in inflammation
Yang, Y., Jiang, G., Zhang, P., & Fan, J. (2015) · Military Medical Research · doi:10.1186/s40779-015-0039-0 · Cited by 291 · see citing works
“These large extracellular structures provide a physical barrier to prevent microbial dissemination and increase the local concentration of antimicrobial effectors [139, 140].”
BackgroundNeutrophil extracellular traps (NETs) - formation and implications.
Zawrotniak, M., & Rąpała‐Kozik, M. (2013) · Acta Biochimica Polonica · doi:10.18388/abp.2013_1983 · Cited by 273 · see citing works
Toxoplasma gondii Triggers Release of Human and Mouse Neutrophil Extracellular Traps
Abdallah, D. S. A., Lin, C., Ball, C. J., King, M. R., Duhamel, G. E., & Denkers, E. (2011) · Infection and Immunity · doi:10.1128/iai.05730-11 · Cited by 264 · see citing works
“The process of NETosis appears to involve histone citrullination-dependent chromatin decondensation and the disintegration of the nuclear membrane, followed by the mixing of nuclear and cytoplasmic effector proteins before eventual release into the extracellular milieu (12, 24, 36, 51).”
BackgroundCathelicidins: Immunomodulatory Antimicrobials
van Harten, R. M., van Woudenbergh, E., van Dijk, A. I. J. M., & Haagsman, H. P. (2018) · Vaccines · doi:10.3390/vaccines6030063 · Cited by 260 · see citing works
“LL-37 and porcine PR-39 can be interwoven in the NETs [51,70].”
BackgroundPapayannopoulos, V., Staab, D., & Zychlinsky, A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028526 · Cited by 252 · see citing works
“in order to trap and kill microbes [8,11].”
Self-citationNADPH Oxidase Inhibits the Pathogenesis of Systemic Lupus Erythematosus
Campbell, A. M., Kashgarian, M. J., & Shlomchik, M. J. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004801 · Cited by 246 · see citing works
“This view has gained wide acceptance (24, 25).”
BackgroundNeutrophil extracellular traps in cancer progression
Cools‐Lartigue, J., Spicer, J. D., Najmeh, S., & Ferri, L. E. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1683-3 · Cited by 236 · see citing works
“Furthermore, NETs are recognized by a number of leukocytes including macrophages and dendritic cells [12, 23, 87, 88].”
BackgroundInfluentialInnate immunity in cystic fibrosis lung disease
Hartl, D., Gaggar, A., Bruscia, E. M., Hector, A., Marcos, V., Jung, A., Greene, C. M., McElvaney, N. G., Mall, M. A., & Döring, G. (2012) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2012.07.003 · Cited by 227 · see citing works
“The mechanisms by which NETs kill the captured and immobilized bacteria are still not fully understood, but histones and granule proteins, such as proteases and calprotectin, could play a role [203,204].”
BackgroundPattern recognition receptor function in neutrophils
Thomas, C. J., & Schroder, K. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.02.008 · Cited by 219 · see citing works
Liu, D., Yang, P.-L., Gao, M., Yu, T., Shi, Y., Zhang, M., Yao, M., Liu, Y., & Zhang, X. (2019) · Clinical science · doi:10.1042/cs20180600 · Cited by 180 · see citing works
Chen, K., Nishi, H., Travers, R. J., Tsuboi, N., Martinod, K., Wagner, D. D., Stan, R. V., Croce, K., & Mayadas, T. N. (2012) · Blood · doi:10.1182/blood-2011-12-401133 · Cited by 218 · see citing works
Neutrophil extracellular traps promote macrophage pyroptosis in sepsis
Chen, L., Zhao, Y., Lai, D., Zhang, P., Yang, Y., Li, Y., Fei, K., Jiang, G., & Fan, J. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0538-5 · Cited by 211 · see citing works
Kambas, K., Mitroulis, I., Apostolidou, E., Girod, A., Chrysanthopoulou, A., Pneumatikos, I. A., Skendros, P., Kourtzelis, I., Koffa, M. D., Kotsianidis, Ι., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045427 · Cited by 209 · see citing works
“Moreover, neutrophils release lytic enzymes for the elimination of extracellular microbes [10].”
BackgroundInfluentialDispersal of Biofilms by Secreted, Matrix Degrading, Bacterial DNase
Nijland, R., Hall, M. J., & Burgess, J. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015668 · Cited by 208 · see citing works
“These are thought to play an important role in capturing invasive pathogens [29].”
BackgroundTreffers, L. W., Hiemstra, I. H., Kuijpers, T. W., van den Berg, T. K., & Matlung, H. L. (2016) · Immunological Reviews · doi:10.1111/imr.12444 · Cited by 204 · see citing works
Meng, W., Paunel‐Görgülü, A., Flohé, S., Hoffmann, A., Witte, I., MacKenzie, C. R., Baldus, S. E., Windolf, J., & Lögters, T. T. (2012) · Critical Care · doi:10.1186/cc11442 · Cited by 200 · see citing works
“The interaction of activated platelets with PMN has been regarded as an important NET-inducing mechanism in sepsis [15].”
BackgroundThe NLRP3/ASC/Caspase‐1 axis regulates IL‐1β processing in neutrophils
Mankan, A. K., Dau, T., Jenne, D. E., & Hornung, V. (2011) · European Journal of Immunology · doi:10.1002/eji.201141921 · Cited by 194 · see citing works
Leishmania donovani Promastigotes Evade the Antimicrobial Activity of Neutrophil Extracellular Traps
Gabriel, C., McMaster, W. R., Girard, D., & Descoteaux, A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000893 · Cited by 192 · see citing works
Vitamin C: a novel regulator of neutrophil extracellular trap formation.
Mohammed, B., Fisher, B., Kraskauskas, D., Farkas, D., Brophy, D., Fowler, A., & Natarajan, R. (2013) · Nutrients · doi:10.3390/nu5083131 · Cited by 187 · see citing works
“In sepsis, NETs are formed in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and interleukin-8 (IL-8) [8,9] by expulsion of genomic DNA into web-like extracellular structures that display antimicrobial proteins such as histones, neutrophil elastase, and myeloperoxidase [10].”
BackgroundImpact of Leishmania metalloprotease GP63 on macrophage signaling
Isnard, A., Shio, M. T., & Olivier, M. (2012) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2012.00072 · Cited by 189 · see citing works
“Interestingly, histones are present in the neutrophil extracellular traps (NETs), as well as in many others antimicrobial components including myeloperoxidase, elastase, and defensin (Papayannopoulos and Zychlinsky, 2009).”
BackgroundA Paradoxical Role for Neutrophils in the Pathogenesis of West Nile Virus
Bai, F., Kong, K., Dai, J., Qian, F., Zhang, L., Brown, C. R., Fikrig, E., & Montgomery, R. R. (2010) · The Journal of Infectious Diseases · doi:10.1086/657416 · Cited by 188 · see citing works
“PMN in WNV Infection • JID 2010:202 (15 December) • 1805 peptides, and produce reactive oxygen species and extracellular traps to combat pathogens [13, 14].”
BackgroundGraphene oxide is degraded by neutrophils and the degradation products are non-genotoxic
Mukherjee, S. P., Gliga, A. R., Lazzaretto, B., Brandner, B. D., Fielden, M. L., Vogt, C., Newman, L., Rodrigues, A. F., Shao, W., Fournier, P. M., et al. (2017) · Nanoscale · doi:10.1039/c7nr03552g · Cited by 188 · see citing works
“Neutrophils employ three strategies to eliminate invading microbes: (1) microbial uptake followed by intracellular destruction through an array of proteolytic and oxidative enzymes, (2) degranulation and secretion of antimicrobial factors such as myeloperoxidase (MPO) leading to extracellular destruction of microbes,…”
BackgroundFunchal, G. A., Jaeger, N., Czepielewski, R. S., Machado, M. S., Muraro, S. P., Stein, R. T., Bonorino, C., & Porto, B. N. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124082 · Cited by 186 · see citing works
Knight, J. S., & Kaplan, M. J. (2012) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e3283546703 · Cited by 185 · see citing works
Neutrophil Extracellular Traps and Endothelial Dysfunction in Atherosclerosis and Thrombosis
Qi, H., Yang, S., & Zhang, L. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00928 · Cited by 186 · see citing works
Clancy, D. M., Sullivan, G. P., Moran, H. B. T., Henry, C. M., Reeves, E. P., McElvaney, N. G., Lavelle, E. C., & Martin, S. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.062 · Cited by 186 · see citing works
“More recent studies also suggest that these cells also form neutrophil extracellular traps (NETs), which also exposes their protease content to the extracellular space (Brinkmann et al., 2004; Papayannopoulos and Zychlinsky, 2009; Kaplan and Radic, 2012).”
BackgroundDAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC
Liaw, P. C., Ito, T., Iba, T., Thachil, J. V., & Zeerleder, S. S. (2015) · Blood Reviews · doi:10.1016/j.blre.2015.12.004 · Cited by 182 · see citing works
“lactoferrin, and calprotectin [26,27].”
Aspergillus fumigatus: contours of an opportunistic human pathogen
McCormick, A., Loeffler, J., & Ebel, F. (2010) · Cellular Microbiology · doi:10.1111/j.1462-5822.2010.01517.x · Cited by 181 · see citing works
“NETs represent an anti-microbial effector mechanism that mediates killing of a diverse range of bacterial pathogens as well as C. albicans (Papayannopoulos and Zychlinsky, 2009).”
BackgroundPinegin, B. V., Vorobjeva, N. V., & Pinegin, V. B. (2015) · Autoimmunity Reviews · doi:10.1016/j.autrev.2015.03.002 · Cited by 178 · see citing works
Zhang, J., Hu, K., Di, L., Wang, P., Liu, Z., Zhang, J., Yue, P., Song, W., Zhang, J., Chen, T., et al. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113964 · Cited by 177 · see citing works
Invertebrate extracellular phagocyte traps show that chromatin is an ancient defence weapon
Robb, C. T., Dyrynda, E. A., Gray, R. D., Rossi, A. G., & Smith, V. J. (2014) · Nature Communications · doi:10.1038/ncomms5627 · Cited by 172 · see citing works
“The discharged chromatin forms complex meshes that ensnare and kill bacteria, fungi, viruses and other parasites 7,9,10 .”
Immune Dysfunction in Uremia 2020
Cohen, G. (2020) · Toxins · doi:10.3390/toxins12070439 · Cited by 172 · see citing works
“NETs also represent a physical barrier and a framework enhancing antimicrobial synergy and reducing harm to host tissues [40].”
BackgroundGray, R. D., Lucas, C. D., Mackellar, A., Li, F., Hiersemenzel, K., Haslett, C., Davidson, D. J., & Rossi, A. G. (2013) · Journal of Inflammation · doi:10.1186/1476-9255-10-12 · Cited by 168 · see citing works
“The beneficial anti-microbial effects of NET formation have been described in several studies [4,20-25].”
BackgroundYuen, J., Pluthero, F. G., Douda, D. N., Riedl, M., Cherry, A., Ulanova, M., Kahr, W. H. A., Palaniyar, N., & Licht, C. P. B. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00137 · Cited by 165 · see citing works
Mycobacterium tuberculosis-Induced Neutrophil Extracellular Traps Activate Human Macrophages
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Innate immunity to intracellular pathogens: macrophage receptors and responses to microbial entry
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“Apart from phagocytosis and degranulation, neutrophils and probably activated macrophages also employ the formation of neutrophil extracellular traps (NETs), which arise from the release of neutrophil nuclear contents into the extracellular space (9, 59).”
BackgroundNeutrophil Extracellular Traps in Sepsis
Camicia, G., Pozner, R. G., & Larrañaga, G. F. D. (2014) · Shock · doi:10.1097/shk.0000000000000221 · Cited by 160 · see citing works
“However, DNases require divalent cations for their activity, providing a potential point of attack by the host (42).”
BackgroundInfluentialHistones trigger sterile inflammation by activating the NLRP 3 inflammasome
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“Two mechanisms are known by which NET is released: (i) pathogenic microorganisms can directly stimulate their release, and (ii) platelets can stimulate the neutrophil to form NET [85].”
BackgroundNew pathophysiological insights and treatment of ANCA-associated vasculitis
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“However, LDH release did increase when macrophages were incubated with a higher dose (5 U) of LKT (Fig.”
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“Neutrophil extracellular traps (NETs) are large extracellular web-like structures comprised of decondensed chromatin and protease that are released by activated neutrophils under certain stimulus [11-14].”
BackgroundNaegleria fowleri : Sources of infection, pathophysiology, diagnosis, and management; a review
Jahangeer, M., Mahmood, Z., Munir, N., Waraich, U., Tahir, I. M., Akram, M., Shah, S. M. A., Zulfqar, A., & Zainab, R. (2019) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13192 · Cited by 144 · see citing works
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How Neutrophil Extracellular Traps Become Visible
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“These antimicrobial components are myeloperoxidase (MPO), neutrophil elastase (NE), cathelicidins like LL-37, histones, proteinase 3, cathepsin, lactoferrin, or gelatinase [3, 16, 17].”
Estradiol-Treated Female Mice as Surrogate Hosts for Neisseria gonorrhoeae Genital Tract Infections
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“PMNs also kill microbes via the release of pre-formed enzymes and antimicrobial peptides and entrapment in neutrophil extracellular traps (NETs) where they are exposed to toxic molecules produced by both pathways (Kobayashi et al., 2005; Papayannopoulos and Zychlinsky, 2009).”
BackgroundNETosis as Source of Autoantigens in Rheumatoid Arthritis
Corsiero, E., Pratesi, F., Prediletto, E., Bombardieri, M., & Migliorini, P. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00485 · Cited by 140 · see citing works
“Arthritis Rheumatol (2014) 66(1):31–9.”
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“that MRP8/14 is a major component of neutrophil extracellular traps (NETs) [24], DNA-networks released by neutrophils that trap microorganisms and facilitate interaction with antimicrobial proteins and thereby bacterial killing [25,26].”
BackgroundEosinophil extracellular DNA traps: molecular mechanisms and potential roles in disease
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Vibrio cholerae Evades Neutrophil Extracellular Traps by the Activity of Two Extracellular Nucleases
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“Antimicrobial strategies of neutrophils range from phagocytosis of the respective microbes to the formation of NETs, which are able to bind and kill pathogens due to a high concentration of antimicrobial compounds [21,22].”
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Extracellular histone release in response to traumatic injury
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“Second, proteomic analysis of circulating biomarkers in lipopolysaccharide (LPS)-induced septic shock has revealed citrullination of extracellular histones as an element of the early response of neutrophils to inflammatory stimuli(30) and the subsequent incorporation of citrullinated histones into NETs in response to…”
BackgroundJovanović, B., Anastasova, L., Rowe, E., Zhang, Y., Clapp, A. R., & Palić, D. (2010) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2010.10.017 · Cited by 132 · see citing works
“NETs release is closely related to the process of respiratory burst and ROS production appears to be a crucial signal involved in initiating the NETosis cell death program (Papayannopoulos and Zychlinsky, 2009).”
Background
- Authors
- Papayannopoulos, V., & Zychlinsky, A.
- Affiliations
- Max Planck Society (DE)
- Corresponding author
- Papayannopoulos, Venizelos
- Venue
- Trends in Immunology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 30
- Issue
- 11
- Pages
- 513-521
- ISSN
- 1471-4906 (ISSN-L)
- OpenAlex
- W2101674426
- Cited by
- 634
- References
- 101
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 28 · 2023: 30 · 2022: 34 · 2021: 31 · 2020: 30 · 2019: 39 · 2018: 45 · 2017: 45 · 2016: 50 · 2015: 35 · 2014: 51 · 2013: 46 · 2012: 68
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Immunology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- neutrophil extracellular traps, neutrophils, innate immunity, antimicrobial peptides, histones, chromatin, antimicrobial synergy
- MeSH terms
- Animals, Bacterial Infections, Chromatin, Histones, Humans, Immunity, Innate, Inflammation, Neutrophils, Phagocytosis, Cell Degranulation, Autoimmunity, Reactive Oxygen Species
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