New insights into neutrophil extracellular traps: Mechanisms of formation and role in inflammation

Frontiers in Immunology

Volumn 7, Issue AUG, 2016, Pages

  Yang, Hang ^a   Biermann, Mona Helena ^b   Brauner, Jan Markus ^b   Liu, Yi ^a   Zhao, Yi ^a   Herrmann, Martin ^b  

^a SICHUAN UNIVERSITY   (China)

^b UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

Antimicrobial activity; Autoimmune diseases; Mitochondrial DNA; NETosis; NETs

Indexed keywords

CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; CATHEPSIN G; HIGH MOBILITY GROUP B2 PROTEIN; HISTONE; LEUKOCYTE ELASTASE; MITOCHONDRIAL DNA; MYELOPEROXIDASE; PROTEIN; REACTIVE OXYGEN METABOLITE;

ANTIMICROBIAL ACTIVITY; AUTOIMMUNE DISEASE; DIABETES MELLITUS; DNA STRAND; EXTRACELLULAR TRAP; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INNATE IMMUNITY; NEOPLASM; NEUTROPHIL; REVIEW; RHEUMATOID ARTHRITIS; SEPSIS; STIMULUS; SYSTEMIC LUPUS ERYTHEMATOSUS; THROMBOSIS; VASCULITIS;

EID: 84989352638     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00302     Document Type: Review

References (91)

1. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science (2004) 303(5663):12-5. doi:10.1126/science.1092385
2. Steinberg BE, Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE (2007) 27(379):pe11. doi:10.1126/stke.3792007pe11
3. Tobias AF, Ulrike A, Christian G, Robert H, Ilka S, Volker W, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol (2007) 176(2):231-41. doi:10.1083/jcb.200606027
4. Takei H, Araki A, Watanabe H, Ichinose A, Sendo F. Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis. J Leukoc Biol (1996) 59(2):229-40
5. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med (2011) 3(73):73ra20. doi:10.1126/scitranslmed.3001201
6. Kessenbrock K, Krumbholz M, Schönermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med (2009) 15(6):623-5. doi:10.1038/nm.1959
7. Sibylla M, Mirjana U, Arezoo D, Patrick AO, Christa B, Martin FF, et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem (2004) 279(42):44123-32. doi:10.1074/jbc.M405883200
8. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med (2007) 13(4):463-9. doi:10.1038/nm1565
9. 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(12):7413-25. doi:10.4049/jimmunol.1000675
10. 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(9):1386-93. doi:10.1038/nm.2847
11. Byrd AS, O'Brien XM, Johnson CM, Lavigne LM, Reichner JS. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. J Immunol (2013) 190(8):4136-48. doi:10.4049/jimmunol.1202671
12. Yipp BG, Kubes P. NETosis: how vital is it? Blood (2013) 122(16):2784-94. doi:10.1182/blood-2013-04-457671
13. Munks MW, McKee AS, Macleod MK, Powell RL, Degen JL, Reisdorph NA, et al. Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood (2010) 116(24):5191-9. doi:10.1182/blood-2010-03-275529
14. Kaplan MJ, Marko R. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol (2012) 189(6):2689-95. doi:10.4049/jimmunol.1201719
15. Papayannopoulos V, Metzler MD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol (2010) 191(3):677-91. doi:10.1083/jcb.201006052
16. Saskia H, John RT, Sanja A, Kerra AM. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. PLoS One (2011) 6(7):e22043. doi:10.1371/journal.pone.0022043
17. Pingxin L, Ming L, Lindberg MR, Kennett MJ, Na X, Yanming W. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med (2010) 207(9):1853-62. doi:10.1084/jem.20100239
18. Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood (2009) 114(13):2619-22. doi:10.1182/blood-2009-05-221606
19. Lim MB, Kuiper JW, Katchky A, Goldberg H, Glogauer M. Rac2 is required for the formation of neutrophil extracellular traps. J Leukoc Biol (2011) 90(4):771-6. doi:10.1189/jlb.1010549
20. Remijsen Q, Vanden BT, Wirawan E, Asselbergh E, Parthoens E, De RR, et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res (2011) 21(2):290-304. doi:10.1038/cr.2010.150
21. Parker H, Dragunow M, Hampton MB, Kettle AJ, Winterbourn CC. Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. J Leukoc Biol (2012) 92(4):841-9. doi:10.1189/jlb.1211601
22. Wang Y, Li M, Sonja S, Sarah C, Pingxin L, Wang DC, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol (2009) 184(2):205-13. doi:10.1083/jcb.200806072
23. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science (2004) 306(5694):279-83. doi:10.1126/science.1101400
24. Kaplan MJ. Neutrophils in the pathogenesis and manifestations of SLE. Nat Rev Rheumatol (2011) 7(12):691-9. doi:10.1038/nrrheum.2011.132
25. White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell (2014) 159(7):1549-62. doi:10.1016/j.cell.2014.11.036
26. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med (2016) 22(2):146-53. doi:10.1038/nm.4027
27. Cardon LR, Burge C, Clayton DA, Karlin S. Pervasive CpG suppression in animal mitochondrial genomes. Proc Natl Acad Sci U S A (1994) 91(9):3799-803. doi:10.1073/pnas.91.9.3799
28. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat Med (2011) 17(11):1381-90. doi:10.1038/nm.2514
29. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature (2010) 464(7285):104-7. doi:10.1038/nature08780
30. Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A (2010) 107(21):9813-8. doi:10.1073/pnas.0909927107
31. Janko C, Schorn C, Grossmayer GE, Frey B, Herrmann M, Gaipl US, et al. Inflammatory clearance of apoptotic remnants in systemic lupus erythematosus (SLE). Autoimmun Rev (2008) 8(1):9-12. doi:10.1016/j.autrev.2008.07.015
32. Eric B, Paul RF. Connective tissue diseases: mitochondria drive NETosis and inflammation in SLE. Nat Rev Rheumatol (2016) 12(4):195-6. doi:10.1038/nrrheum.2016.24
33. Haiting W, Ting L, Sheng C, Yueying G, Shuang Y. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol (2015) 67(12):3190-200. doi:10.1002/art.39296
34. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) (2012) 122(6):253-70. doi:10.1042/CS20110386
35. von Kökritz-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(6):3070-80. doi:10.1182/blood-2007-07-104018
36. 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(4):401-7. doi:10.1016/j.cub.2006.01.056
37. Juneau RA, Pang B, Weimer KE, Armbruster CE, Swords WE. Non typeable Haemophilus influenzae initiates formation of neutrophil extracellular traps. Infect Immun (2011) 79(1):431-8. doi:10.1128/IAI.00660-10
38. Munafo DB, Johnson JL, Brzezinska AA, Ellis BA, Wood MR, Catz SD. DNase I inhibits a late phase of reactive oxygen species production in neutrophils. J Innate Immun (2009) 1(6):527-42. doi:10.1159/000235860
39. Ramos KV, Mondragón F, Mondragón CM, Gonzalez PS, Muñiz HS, Rojas EO, et al. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Edinb) (2009) 89(1):29-37. doi:10.1016/j.tube.2008.09.009
40. McCormick A, Heesemann L, Wagener J, Marcos V, Hartl D, Loeffler J, et al. NETs formed by human neutrophils inhibit growth of the pathogenic mold Aspergillus fumigatus. Microbes Infect (2010) 12(12-13):928-36. doi:10.1016/j.micinf.2010.06.009
41. Bianchi M, Niemiec MJ, Siler U, Urban CF, Reichenbach J. Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. J Allergy Clin Immunol (2011) 127(5):1243.e-52.e. doi:10.1016/j.jaci.2011.01.021
42. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol (2006) 8(4):668-76. doi:10.1111/j.1462-5822.2005.00659.x
43. Delbosc S, Alsac JM, Journe C, Louedec L, Castier Y, Bonnaure-Mallet M, et al. Porphyromonas gingivalis participates in pathogenesis of human abdominal aortic aneurysm by neutrophil activation: proof of concept in rats. PLoS One (2011) 6(4):e18679. doi:10.1371/journal.pone.0018679
44. Renzo M, Eva D, Pietro D. Killing by neutrophil extracellular traps: fact or folklore? Blood (2012) 119(5):1214-6. doi:10.1182/blood-2011-07-364604
45. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol (2014) 15(11):1017-25. doi:10.1038/ni.2987
46. Averhoff P, Kolbe M, Zychlinsky A, Weinrauch Y. Single residue determines the specificity of neutrophil elastase for Shigella virulence factors. J Mol Biol (2008) 377(4):1053-66. doi:10.1016/j.jmb.2007.12.034
47. Parker H, Albrett AM, Kettle AJ, Winterbourn CC. Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide. J Leukoc Biol (2012) 91(3):369-76. doi:10.1189/jlb.0711387
48. 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(10):e1000639. doi:10.1371/journal.ppat.1000639
49. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol (2007) 5(8):577-82. doi:10.1038/nrmicro1710
50. Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, Normark S, et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol (2007) 9(5):1162-71. doi:10.1111/j.1462-5822.2006.00857.x
51. Seper A, Hosseinzadeh A, Gorkiewicz G, Lichtenegger S, Roier S, Leitner DR, et al. Vibrio cholerae evades neutrophil extracellular traps by the activity of two extracellular nucleases. PLoS Pathog (2013) 9(9):e1003614. doi:10.1371/journal.ppat.1003614
52. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques NB. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol (2006) 16(4):401-7. doi:10.1016/j.cub.2006.01.056
53. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol (2006) 16(4):396-400. doi:10.1016/j.cub.2005.12.039
54. Möllerherm H, Neumann A, Schilcher K, Blodkamp S, Zeitouni NE, Dersch P, et al. Yersinia enterocolitica-mediated degradation of neutrophil extracellular traps. FEMS Microbiol Lett (2015) 362(23):fnv192. doi:10.1093/femsle/fnv192
55. Derré-Bobillot A, Cortes-Perez NG, Yamamoto Y, Kharrat P, Couvé E, Da Cunha V. Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence. Mol Microbiol (2013) 89(3):518-31. doi:10.1111/mmi.12295
56. de Buhr N, Neumann A, Jerjomiceva N, von Köckritz-Blickwede M, Baums CG. Streptococcus suis DNase SsnA contributes to degradation of neutrophil extracellular traps (NETs) and evasion of NET-mediated antimicrobial activity. Microbiology (2014) 160(Pt2):385-95. doi:10.1099/mic.0.072199-0
57. Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J Innate Immun (2010) 2(6):576-86. doi:10.1159/000319909
58. Brogden G, von Köckritz-Blickwede M, Adamek M, Reuner F, Jung SV, Naim HY, et al. β-Glucan protects neutrophil extracellular traps against degradation by Aeromonas hydrophila in carp (Cyprinuscarpio). Fish Shellfish Immunol (2012) 33(4):1060-4. doi:10.1016/j.fsi.2012.08.009
59. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med (1997) 337(21):1512-23. doi:10.1056/NEJM199711203372106
60. Söderberg D, Kurz T, Motamedi A, Hellmark T, Eriksson P, Segelmark M. Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission. Rheumatology (Oxford) (2015) 54(11):2085-94. doi:10.1093/rheumatology/kev217
61. Lögters T, Margraf S, Altrichter J, Cinatl J, Mitzner S, Windolf J, et al. The clinical value of neutrophil extracellular traps. Med Microbiol Immunol (2009) 198(4):211-9. doi:10.1007/s00430-009-0121-x
62. Aparna M, Martin H, Luis EM. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol (2016) 8(7):35. doi:10.3389/fimmu.2016.00035
63. Niewold TB, Clark DN, Salloum R, Poole BD. Interferon alpha in systemic lupus erythematosus. J Biomed Biotechnol (2010) 2010:948364. doi:10.1155/2010/948364
64. Farrera C, Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol (2013) 191(5):2647-56. doi:10.4049/jimmunol.1300436
65. Martinez VF, Balada E, Ordi RJ, Bujan RS, Sellas FA, Vilardell TM. DNase 1 activity in patients with systemic lupus erythematosus: relationship with epidemiological, clinical, immunological and therapeutical features. Lupus (2009) 18(5):418-23. doi:10.1177/0961203308098189
66. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet (2001) 28(4):313-4. doi:10.1038/91070
67. Frost PG, Lachmann PJ. The relationship of desoxyribonuclease inhibitor levels in human sera to the occurrence of antinuclear antibodies. Clin Exp Immunol (1968) 3(5):447-445
68. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol (2011) 187(1):538-52. doi:10.4049/jimmunol.1100450
69. 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(73):73ra19. doi:10.1126/scitranslmed.3001180
70. Leffler J, Martin M, Gullstrand B, Tydén H, Lood C, Truedsson L, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol (2012) 188(7):3522-31. doi:10.4049/jimmunol.1102404
71. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A (2010) 107(36):15880-5. doi:10.1073/pnas.1005743107
72. 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(8):887-96. doi:10.1038/nm.2184
73. von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med (2012) 209(4):819-35. doi:10.1084/jem.20112322
74. Swystun LL, Mukherjee S, Liaw PC. Breast cancer chemotherapy induces the release of cell-free DNA, a novel procoagulant stimulus. J Thromb Haemost (2011) 9(11):2313-21. doi:10.1111/j.1538-7836.2011.04465.x
75. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A (2007) 104(15):6388-93. doi:10.1073/pnas.0608647104
76. Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One (2012) 7(2):e32366. doi:10.1371/journal.pone.0032366
77. Jun X, Xiaomei Z, Rosana P, Marc M, Concetta TA, Fabrizio S, et al. Extracellular histones are major mediators of death in sepsis. Nat Med (2009) 15(11):1318-21. doi:10.1038/nm.2053
78. Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood (2011) 118(7):1952-61. doi:10.1182/blood-2011-03-343061
79. Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost (2011) 9(9):1795-803. doi:10.1111/j.1538-7836.2011.04422.x
80. Demers M, Wagner DD. NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost (2014) 40(3):277-83. doi:10.1055/s-0034-1370765
81. Dwivedi N, Upadhyay J, Neeli I, Khan S, Pattanaik D, Myers L, et al. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular traps. Arthritis Rheum (2011) 64(4):982-92. doi:10.1002/art.33432
82. Ritika K, Carmelo CR, Anuradha VG, Alison G, Srilakshmi Y, Jason SK, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med (2013) 5(178):178ra140. doi:10.1126/scitranslmed.3005580
83. Hanses F, Park S, Rich J, Lee JC. Reduced neutrophil apoptosis in diabetic mice during staphylococcal infection leads to prolonged TNFa production and reduced neutrophil clearance. PLoS One (2011) 6(8):e23633. doi:10.1371/journal.pone.0023633
84. Krystallenia IA, Christina P, Panayiotis DZ, Nikolaos VA, Konstantinos M, Vassiliki S, et al. Cytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation. J Clin Immunol (2008) 28(4):314-21. doi:10.1007/s10875-007-9164-1
85. 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(7):815-9. doi:10.1038/nm.3887
86. Ho-Tin-Noé B, Carbo C, Demers M, Cifuni SM, Goerge T, Wagner DD. Innate immune cells induce hemorrhage in tumors during thrombocytopenia. Am J Pathol (2009) 175(4):1699-708. doi:10.2353/ajpath.2009.090460
87. 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 immune editing. Front Immunol (2013) 4:48. doi:10.3389/fimmu.2013.00048
88. 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(8):3446-58. doi:10.1172/JCI67484
89. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med (2009) 15(11):1318-21. doi:10.1038/nm.2053
90. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol (2013) 13(1):34-45. doi:10.1038/nri3345
91. Martinod K, Fuchs TA, Zitomersky NL, Wong SL, Demers M, Gallant M, et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood (2015) 125(12):1948-56. doi:10.1182/blood-2014-07-587709