Front Immunol 10: 2536

DAMPs and NETs in Sepsis

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^{Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States}

^{Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States}

^{Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States}

^{Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States}

Edited by: Timothy Robert Billiar, University of Pittsburgh, United States

Reviewed by: Markus Bosmann, Boston University, United States; Michael Thomas Lotze, University of Pittsburgh Cancer Institute, United States

*Correspondence: Monowar Aziz ude.llewhtron@1zizam

Ping Wang ude.llewhtron@gnawp

This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

Edited by: Timothy Robert Billiar, University of Pittsburgh, United States

Reviewed by: Markus Bosmann, Boston University, United States; Michael Thomas Lotze, University of Pittsburgh Cancer Institute, United States

Received 2019 May 14; Accepted 2019 Oct 11.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.

Keywords: DAMPs (damage-associated molecular patterns), NETs (neutrophil extracellular traps), sepsis, HMGB1 (high-mobility group box 1), CIRP, cold-inducible RNA-binding protein, histone, neutrophils

Abstract

Footnotes

Funding. This study was supported by the National Institutes of Health (NIH) grant R35GM118337 (PW) and R01GM129633 (MA).

Footnotes

References

1. Rhee C, Jones TM, Hamad Y, Pande A, Varon J, O'Brien C, et al. . Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals. JAMA Netw Open. (2019) 2:e187571. 10.1001/jamanetworkopen.2018.7571 ] [
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. (2016) 315:801–10. 10.1001/jama.2016.0287 ] [[Google Scholar]
3. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. . Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am J Respir Crit Care Med. (2016) 193:259–72. 10.1164/rccm.201504-0781OC [] [[PubMed]
4. Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. (2013) 93:329–42. 10.1189/jlb.0912437 ] [
5. Cabrera-Perez J, Badovinac VP, Griffith TS. Enteric immunity, the gut microbiome, and sepsis, Rethinking the germ theory of disease. Exp Biol Med. (2017) 242:127–39. 10.1177/1535370216669610 ] [
6. Gentile LF, Moldawer LL. DAMPS, PAMPS and the origins of SIRS in bacterial sepsis. Shock. (2013) 39:113–4. 10.1097/SHK.0b013e318277109c ] [
7. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. (2010) 140:805–20. 10.1016/j.cell.2010.01.022 [] [[PubMed]
8. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. (1994) 12:991–1045. 10.1146/annurev.iy.12.040194.005015 [] [[PubMed]
9. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. (2004) 4:469–78. 10.1038/nri1372 [] [[PubMed]
10. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. (2007) 28:429–36. 10.1016/j.it.2007.08.004 [] [[PubMed]
11. McCarthy G, Goulopoulou S, Wenceslau CF, Spitler K, Matsumoto T, Webb RC. Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension. Am J Physiol Heart Circ Physiol. (2014) 306:H184–96. 10.1152/ajpheart.00328.2013 ] [
12. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al. . Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. (2005) 33:564–73. 10.1097/01.CCM.0000155991.88802.4D [] [[PubMed]
13. Zhou Y, Dong H, Zhong Y, Huang J, Lv J, Li J. The Cold-Inducible RNA-Binding Protein (CIRP) level in peripheral blood predicts sepsis outcome. PLoS ONE. (2015) 10:e0137721. 10.1371/journal.pone.0137721 ] [
14. Ekaney ML, Otto GP, Sossdorf M, Sponholz C, Boehringer M, Loesche W, et al. . Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation. Crit Care. (2014) 18:543. 10.1186/s13054-014-0543-8 ] [
15. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. (2013) 13:159–75. 10.1038/nri3399 [] [[PubMed]
16. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. (2018) 18:134–47. 10.1038/nri.2017.105 [] [[PubMed]
17. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. . Neutrophil extracellular traps kill bacteria. Science. (2004) 303:1532–5. 10.1126/science.1092385 [] [[PubMed]
18. Li RHL, Tablin F. A comparative review of neutrophil extracellular traps in sepsis. Front Vet Sci. (2018) 5:291. 10.3389/fvets.2018.00291 ] [
19. Schaefer L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem. (2014) 289:35237–45. 10.1074/jbc.R114.619304 ] [
20. Brinkmann V. Neutrophil extracellular traps in the second decade. J Innate Immun. (2018) 10:414–21. 10.1159/000489829 ] [
21. Sessa L, Bianchi ME. The evolution of High Mobility Group Box (HMGB) chromatin proteins in multicellular animals. Gene. (2007) 387:133–40. 10.1016/j.gene.2006.08.034 [] [[PubMed]
22. Venkatesh SJL. Workman. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol. (2015) 16:178–89. 10.1038/nrm3941 [] [[PubMed]
23. Marsman G, Zeerleder S, Luken BM. Extracellular histones, cell-free DNA, or nucleosomes: differences in immunostimulation. Cell Death Dis. (2016) 7:e2518. 10.1038/cddis.2016.410 ] [
24. Lee W, Yuseok O, Yang S, Lee BS, Lee JH, Park EK, et al. . JH-4 reduces HMGB1-mediated septic responses and improves survival rate in septic mice. J Cell Biochem. (2019) 120:6277–89. 10.1002/jcb.27914 [] [[PubMed]
25. Musumeci D, Roviello GN, Montesarchio D. An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther. (2014) 141:347–57. 10.1016/j.pharmthera.2013.11.001 [] [[PubMed]
26. Wellmann S, Buhrer C, Moderegger E, Zelmer A, Kirschner R, Koehne P, et al. . Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism. J Cell Sci. (2004) 117(Pt 9):1785–94. 10.1242/jcs.01026 [] [[PubMed]
27. Ward PA, Fattahi F. New strategies for treatment of infectious sepsis. J Leukoc Biol. (2019) 106:187–92. 10.1002/JLB.4MIR1118-425R [] [[PubMed]
28. Rhodes A, Wort SJ, Thomas H, Collinson P, Bennett ED. Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Crit Care. (2006) 10:R60. 10.1186/cc4894 ] [
29. Rios-Toro JJ, Marquez-Coello M, Garcia-Alvarez JM, Martin-Aspas A, Rivera-Fernandez R, Saez de Benito A, Giron-Gonzalez JA. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock. PLoS ONE. (2017) 12:e0175254. 10.1371/journal.pone.0175254 ] [
30. Hoogerwerf JJ, Tanck MWT, van Zoelen MAD, Wittebole X, Laterre PF, van der Poll T. Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med. (2010) 36:630–7. 10.1007/s00134-010-1773-0 ] [
31. 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. 10.1038/nm.3887 ] [
32. Murthy P, Singhi AD, Ross MA, Loughran P, Paragomi P, Papachristou GI, et al. . Enhanced neutrophil extracellular trap formation in acute pancreatitis contributes to disease severity and is reduced by chloroquine. Front Immunol. (2019) 10:28. 10.3389/fimmu.2019.00028 ] [
33. Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. (2016) 30:257–61. 10.1016/j.blre.2015.12.004 [] [[PubMed]
34. Martin SJ. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system. FEBS J. (2016) 283:2599–615. 10.1111/febs.13775 [] [[PubMed]
35. van Golen RF, Reiniers MJ, Marsman G, Alles LK, van Rooyen DM, Petri BVA, et al. . The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion. Biochim Biophys Acta Mol Basis Dis. (2019) 1865:1192–200. 10.1016/j.bbadis.2019.01.014 [] [[PubMed]
36. McGinn JT, Aziz M, Zhang F, Yang WL, Nicastro JM, Coppa GF, et al. . Cold-inducible RNA-binding protein-derived peptide C23 attenuates inflammation and tissue injury in a murine model of intestinal ischemia-reperfusion. Surgery. (2018) 164:1191–7. 10.1016/j.surg.2018.06.048 ] [
37. Tian Y, Charles EJ, Yan Z, Wu D, French BA, Kron IL, et al The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1-receptor for advanced glycation end products-Toll-like receptor 9 pathway. J Thorac Cardiovasc Surg. (2018) 15:2256–69.e3. 10.1016/j.jtcvs.2018.09.043 ] [[Google Scholar]
38. Mihm S. Danger-Associated Molecular Patterns (DAMPs): molecular triggers for sterile inflammation in the liver. Int J Mol Sci. (2018) 19:E3104. 10.3390/ijms19103104 ] [
39. Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev. (2015) 24(Pt. A):29–39. 10.1016/j.arr.2015.01.003 [] [[PubMed]
40. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. (2002) 418:191–5. 10.1038/nature00858 [] [[PubMed]
41. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. . HMG-1 as a late mediator of endotoxin lethality in mice. Science. (1999) 285:248–51. 10.1126/science.285.5425.248 [] [[PubMed]
42. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. (2018) 18:e27. 10.4110/in.2018.18.e27 ] [
43. Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, et al. . Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. (2013) 19:1489–95. 10.1038/nm.3368 ] [
44. Aziz M, Brenner M, Wang P. Extracellular CIRP (eCIRP) and inflammation. J Leukoc Biol. (2019) 106:133–46. 10.1002/JLB.3MIR1118-443R ] [
45. Lu B, Wang C, Wang M, Li W, Chen F, Tracey KJ, Wang H. Molecular mechanism and therapeutic modulation of hmgb1 release and action: an updated review. Expert Rev Clin Immunol. (2014) 10:713–27. 10.1586/1744666X.2014.909730 ] [
46. Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. (2018) 22:263–77. 10.1080/14728222.2018.1439924 [] [[PubMed]
47. Janko C, Filipovic M, Munoz LE, Schorn C, Schett G, Ivanovic-Burmazovic I, et al. . Redox modulation of HMGB1-related signaling. Antioxid Redox Signal. (2014) 20:1075–85. 10.1089/ars.2013.5179 ] [
48. Abdulmahdi W, Patel D, Rabadi MM, Azar T, Jules E, Lipphardt M, et al. . HMGB1 redox during sepsis. Redox Biol. (2017) 13:600–7. 10.1016/j.redox.2017.08.001 ] [
49. Wang H, Ward MF, Sama AE. Targeting HMGB1 in the treatment of sepsis. Expert Opin Ther Targets. (2014) 18:257–68. 10.1517/14728222.2014.863876 ] [
50. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol. (2000) 165:2950–4. 10.4049/jimmunol.165.6.2950 [] [[PubMed]
51. Anggayasti WL, Mancera RL, Bottomley S, Helmerhorst E. The self-association of HMGB1 and its possible role in the binding to DNA and cell membrane receptors. FEBS Lett. (2017) 591:282–94. 10.1002/1873-3468.12545 [] [[PubMed]
52. Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol. (2008) 180:5067–74. 10.4049/jimmunol.180.7.5067 [] [[PubMed]
53. Kwak MS, Lim M, Lee YJ, Lee HS, Kim YH, Youn JH, et al. . HMGB1 binds to lipoteichoic acid and enhances TNF-alpha and IL-6 production through HMGB1-mediated transfer of lipoteichoic acid to CD14 and TLR2. J Innate Immun. (2015) 7:405–16. 10.1159/000369972 ] [
54. Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. (2012) 72:3977–86. 10.1158/0008-5472.CAN-12-0938 ] [
55. Angus DC, Yang L, Kong L, Kellum JA, Delude RL, Tracey KJ, et al. . Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med. (2007) 35:1061–7. 10.1097/01.CCM.0000259534.68873.2A [] [[PubMed]
56. Stevens NE, Chapman MJ, Fraser CK, Kuchel TR, Hayball JD, Diener KR. Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes. Sci Rep. (2017) 7:5850. 10.1038/s41598-017-06205-z ] [
57. Lee W, Ku SK, Bae JS. Zingerone reduces HMGB1-mediated septic responses and improves survival in septic mice. Toxicol Appl Pharmacol. (2017) 329:202–11. 10.1016/j.taap.2017.06.006 [] [[PubMed]
58. De Leeuw F, Zhang T, Wauquier C, Huez G, Kruys V, Gueydan C. The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor. Exp Cell Res. (2007) 313:4130–44. 10.1016/j.yexcr.2007.09.017 [] [[PubMed]
59. Xue JH, Nonoguchi K, Fukumoto M, Sato T, Nishiyama H, Higashitsuji H, et al. . Effects of ischemia and H2O2 on the cold stress protein CIRP expression in rat neuronal cells. Free Radic Biol Med. (1999) 27:1238–44. 10.1016/S0891-5849(99)00158-6 [] [[PubMed]
60. Sheikh MS, Carrier F, Papathanasiou MA, Hollander MC, Zhan Q, Yu K, et al. . Identification of several human homologs of hamster DNA damage-inducible transcripts. Cloning and characterization of a novel UV-inducible cDNA that codes for a putative RNA-binding protein. J Biol Chem. (1997) 272:26720–6. 10.1074/jbc.272.42.26720 [] [[PubMed]
61. Ward PA. An endogenous factor mediates shock-induced injury. Nat Med. (2013) 19:1368–9. 10.1038/nm.3387 [] [[PubMed]
62. Zhu X, Bührer C, Wellmann S. Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cell Mol Life Sci. (2016) 73:3839–59. 10.1007/s00018-016-2253-7 ] [
63. Li Z, Fan EK, Liu J, Scott MJ, Li Y, Li S, et al. . Cold-inducible RNA-binding protein through TLR4 signaling induces mitochondrial DNA fragmentation and regulates macrophage cell death after trauma. Cell Death Dis. (2017) 8:e2775. 10.1038/cddis.2017.187 ] [
64. Khan MM, Yang WL, Brenner M, Bolognese AC, Wang P. Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Sci Rep. (2017) 7:41363. 10.1038/srep41363 ] [
65. Yang WL, Sharma A, Wang Z, Li Z, Fan J, Wang P. Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Sci Rep. (2016) 6:26571. 10.1038/srep26571 ] [
66. McGinn J, Zhang F, Aziz M, Yang WL, Nicastro J, Coppa GF, et al. . The protective effect of a short peptide derived from cold-inducible RNA-binding protein in renal ischemia-reperfusion injury. Shock. (2018) 49:269–76. 10.1097/SHK.0000000000000988 ] [
67. Godwin A, Yang WL, Sharma A, Khader A, Wang Z, Zhang F, et al. . Blocking cold-inducible RNA-binding protein protects liver from ischemia-reperfusion injury. Shock. (2015) 43:24–30. 10.1097/SHK.0000000000000251 ] [
68. Zhang F, Brenner M, Yang WL, Wang P. A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice. Sci Rep. (2018) 8:3052. 10.1038/s41598-017-13139-z ] [
69. Denning NL, Yang WL, Hansen L, Prince J, Wang P. C23, an oligopeptide derived from cold-inducible RNA-binding protein, suppresses inflammation and reduces lung injury in neonatal sepsis. J Pediatr Surg. (2019). 10.1016/j.jpedsurg.2018.12.020. [Epub ahead of print]. ] [
70. Szatmary P, Huang W, Criddle D, Tepikin A, Sutton R. Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders. J Cell Mol Med. (2018) 22:4617–29. 10.1111/jcmm.13797 ] [
71. 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) 15:1318–21. 10.1038/nm.2053 ] [
72. Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. (2011) 187:2626–31. 10.4049/jimmunol.1003930 ] [
73. Alhamdi Y, Abrams ST, Cheng Z, Jing S, Su D, Liu Z, et al. . Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. (2015) 43:2094–103. 10.1097/CCM.0000000000001162 [] [[PubMed]
74. Magna M, Pisetsky DS. The alarmin properties of DNA and DNA-associated Nuclear Proteins. Clin Ther. (2016) 38:1029–41. 10.1016/j.clinthera.2016.02.029 [] [[PubMed]
75. Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL, Weitz JI, et al. . Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. (2012) 16:R151. 10.1186/cc11466 ] [
76. Li Y, Berke IC, Modis Y. DNA binding to proteolytically activated TLR9 is sequence-independent and enhanced by DNA curvature. Embo J. (2012) 31:919–31. 10.1038/emboj.2011.441 ] [
77. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. . Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. (2010) 464:104–7. 10.1038/nature08780 ] [
78. Bhagirath VC, Dwivedi DJ, Liaw PC. Comparison of the proinflammatory and procoagulant properties of nuclear, mitochondrial, and bacterial DNA. Shock. (2015) 44:265–71. 10.1097/SHK.0000000000000397 [] [[PubMed]
79. Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol. (2004) 75:995–1000. 10.1189/jlb.0703328 [] [[PubMed]
80. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. (2006) 368:157–69. 10.1016/S0140-6736(06)69005-3 [] [[PubMed]
81. Blasius L, Beutler B. Intracellular toll-like receptors. Immunity. (2010) 32:305–15. 10.1016/j.immuni.2010.03.012 [] [[PubMed]
82. Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, et al. . ATP synthesis and storage. Purinergic Signal. (2012) 8:343–57. 10.1007/s11302-012-9305-8 ] [
83. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. (2013) 38:209–23. 10.1016/j.immuni.2013.02.003 [] [[PubMed]
84. Vénéreau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. (2015) 6:422. 10.3389/fimmu.2015.00422 ] [
85. Zha QB, Wei HX, Li CG, Liang YD, Xu LH, Bai WJ, et al. . ATP-induced inflammasome activation and pyroptosis is regulated by AMP-activated protein kinase in macrophages. Front Immunol. (2016) 7:597. 10.3389/fimmu.2016.00597 ] [
86. Gombault A, Baron L, Couillin I. ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol. (2012) 3:414. 10.3389/fimmu.2012.00414 ] [
87. Ledderose A, Bao Y, Kondo Y, Fakhari M, Slubowski C, Zhang J, Junger WG. Purinergic signaling and immune responses in sepsis. Clin Ther. (2016) 38:1054–65. 10.1016/j.clinthera.2016.04.002 ] [
88. Sueyoshi K, Ledderose C, Shen Y, Lee AH, Shapiro NI, Junger WG. Lipopolysaccharide suppresses T cells by generating extracellular ATP that impairs their mitochondrial function via P2Y11 receptors. J Biol Chem. (2019) 294:6283–93. 10.1074/jbc.RA118.007188 ] [
89. Savio LEB, de Andrade Mello P, Figliuolo VR, de Avelar Almeida TF, Santana PT, Oliveira SDS, et al. . Coutinho-Silva. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. J Hepatol. (2017) 67:716–26. 10.1016/j.jhep.2017.05.021 ] [
90. Cauwels, Rogge E, Vandendriessche B, Shiva S, Brouckaert P. Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis. (2014) 5:e1102. 10.1038/cddis.2014.70 ] [
91. Pugin J, Stern-Voeffray S, Daubeuf B, Matthay MA, Elson G, Dunn-Siegrist I. Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. Blood. (2004) 104:4071–9. 10.1182/blood-2003-04-1290 [] [[PubMed]
92. Gibot S, Kolopp-Sarda MN, Bene MC, Bollaert PE, Lozniewski A, Mory F, et al. . A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J Exp Med. (2004) 200:1419–26. 10.1084/jem.20040708 ] [
93. Benz F, Roy S, Trautwein C, Roderburg C, Luedde T. Circulating MicroRNAs as biomarkers for sepsis. Int J Mol Sci. (2016) 17:E78. 10.3390/ijms17010078 ] [
94. Real JM, Ferreira LRP, Esteves GH, Koyama FC, Dias MVS, Bezerra-Neto JE, et al. . Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?Crit Care. (2018) 22:68. 10.1186/s13054-018-2003-3 ] [
95. Xu J, Feng Y, Jeyaram A, Jay SM, Zou L, Chao W. Circulating plasma extracellular vesicles from septic mice induce inflammation via MicroRNA- and TLR7-dependent mechanisms. J Immunol. (2018) 2018:ji1801008 10.4049/jimmunol.1801008 ] [
96. Rider P, Voronov E, Dinarello CA, Apte RN, Cohen I. Alarmins: feel the stress. J Immunol. (2017) 198:1395–402. 10.4049/jimmunol.1601342 [] [[PubMed]
97. Yu Y, Tang D, Kang R. Oxidative stress-mediated HMGB1 biology. Front Physiol. (2015) 6:93. 10.3389/fphys.2015.00093 ] [
98. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol. (2009) 9:447–53. 10.1016/j.coph.2009.04.008 ] [
99. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. (2011) 1813:878–88. 10.1016/j.bbamcr.2011.01.034 [] [[PubMed]
100. Mishra HK, Ma J, Walcheck B. Ectodomain shedding by ADAM17: its role in neutrophil recruitment and the impairment of this process during sepsis. Front Cell Infect Microbiol. (2017) 7:138. 10.3389/fcimb.2017.00138 ] [
101. Bouchon, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. (2001) 410:1103–7. 10.1038/35074114 [] [[PubMed]
102. Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood. (2007) 110:1029–35. 10.1182/blood-2007-01-069195 [] [[PubMed]
103. Xi H, Katschke KJ, Jr, Li Y, Truong T, Lee WP, Diehl L, et al. . IL-33 amplifies an innate immune response in the degenerating retina. J Exp Med. (2016) 213:189–207. 10.1084/jem.20150894 ] [
104. Nair RR, Mazza D, Brambilla F, Gorzanelli A, Agresti A, Bianchi ME. LPS-challenged macrophages release microvesicles coated with histones. Front Immunol. (2018) 9:1463. 10.3389/fimmu.2018.01463 ] [
105. Jiao Y, Li Z, Loughran PA, Fan EK, Scott MJ, Li Y, et al. . Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock. J Leukoc Biol. (2018) 103:175–83. 10.1189/jlb.3HI0517-173R ] [
106. Miksa M, Wu R, Dong W, Das P, Yang D, Wang P. Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. Shock. (2006) 25:586–93. 10.1097/01.shk.0000209533.22941.d0 [] [[PubMed]
107. Szatmary C, Nossal R, Parent CA, Majumdar R. Modeling neutrophil migration in dynamic chemoattractant gradients: assessing the role of exosomes during signal relay. Mol Biol Cell. (2017) 28:3457–70. 10.1091/mbc.e17-05-0298 ] [
108. Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. (2008) 214:199–210. 10.1002/path.2277 ] [
109. Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. (2011) 41:271–90. 10.1007/s00726-010-0689-x ] [
110. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, friends. J Cell Biol. (2013) 200:373–83. 10.1083/jcb.201211138 ] [
111. Collett GP, Redman CW, Sargent IL, Vatish M. Endoplasmic reticulum stress stimulates the release of extracellular vesicles carrying danger-associated molecular pattern (DAMP) molecules. Oncotarget. (2018) 9(6):6707–17. 10.18632/oncotarget.24158 ] [
112. Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutat Res. (2011) 717:85–90. 10.1016/j.mrfmmm.2011.03.004 ] [
113. Feng Y, Zou L, Yan D, Chen H, Xu G, Jian W, et al. . Extracellular MicroRNAs induce potent innate immune responses via TLR7/MyD88-dependent mechanisms. J Immunol. (2017) 199:2106–17. 10.4049/jimmunol.1700730 ] [
114. Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annu Rev Pathol. (2014) 9:181–218. 10.1146/annurev-pathol-020712-164023 ] [
115. Cooper PR, Palmer LJ, Chapple IL. Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe?Periodontol 2000. (2013) 63:165–97. 10.1111/prd.12025 [] [[PubMed]
116. Carmona-Rivera C, Kaplan MJ. Induction and quantification of NETosis. Curr Protoc Immunol. (2016) 115:14.41.1–14. 10.1002/cpim.16 [] [[PubMed]
117. Chapman EA, Lyon M, Simpson D, Mason D, Beynon RJ, Moots RJ, et al. . Caught in a Trap? proteomic analysis of neutrophil extracellular traps in rheumatoid arthritis and systemic lupus erythematosus. Front Immunol. (2019) 10:423. 10.3389/fimmu.2019.00423 ] [
118. de Buhr N, von Köckritz-Blickwede M. How neutrophil extracellular traps become visible. J Immunol Res. (2016) 2016:4604713. 10.1155/2016/4604713 ] [
119. Zharkova O, Tay SH, Lee HY, Shubhita T, Ong WY, Lateef A, et al. . A flow cytometry-based assay for high-throughput detection and quantification of neutrophil extracellular traps in mixed cell populations. Cytometry A. (2019) 95:268–78. 10.1002/cyto.a.23672 ] [
120. Gavillet M, Martinod K, Renella R, Harris C, Shapiro NI, Wagner DD, et al. . Flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples. Am J Hematol. (2015) 90:1155–8. 10.1002/ajh.24185 ] [
121. Ginley BG, Emmons T, Lutnick B, Urban CF, Segal BH, Sarder P. Computational detection and quantification of human and mouse neutrophil extracellular traps in flow cytometry and confocal microscopy. Sci Rep. (2017) 7:17755. 10.1038/s41598-017-18099-y ] [
122. Thålin C, Daleskog M, Göransson SP, Schatzberg D, Lasselin J, Laska AC, et al. . Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma. Immunol Res. (2017) 65:706–12. 10.1007/s12026-017-8905-3 ] [
123. 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. 10.1038/cgt.2015.21 ] [
124. Yipp BG, Kubes P. NETosis: how vital is it?Blood. (2013) 122:2784–94. 10.1182/blood-2013-04-457671 [] [[PubMed]
125. Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M. New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation. Front Immunol. (2016) 7:302. 10.3389/fimmu.2016.00302 ] [
126. Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, Alvarado-Navarro A, Fafutis-Morris M. Neutrophil extracellular traps and its implications in inflammation: an overview. Front Immunol. (2017) 8:81. 10.3389/fimmu.2017.00081 ] [
127. 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. 10.1038/nm.2847 ] [
128. Manda, Pruchniak MP, Arazna M, Demkow UA. Neutrophil extracellular traps in physiology and pathology. Cent Eur J Immunol. (2014) 39:116–21. 10.5114/ceji.2014.42136 ] [
129. 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. 10.1038/cdd.2009.96 [] [[PubMed]
130. Itagaki K, Kaczmarek E, Lee YT, Tang IT, Isal B, Adibnia Y, et al. . Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS ONE. (2015) 10:e0120549. 10.1371/journal.pone.0120549 ] [
131. McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, et al. . Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J Crit Care. (2014) 29:1133.e1–5. 10.1016/j.jcrc.2014.07.013 [] [[PubMed]
132. 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. 10.1189/jlb.3A0415-161R [] [[PubMed]
133. Amulic A, Knackstedt SL, Abu Abed U, Deigendesch N, Harbort CJ, Caffrey BE, et al. . Cell-cycle proteins control production of neutrophil extracellular traps. Dev Cell. (2017) 43:449–62.e5. 10.1016/j.devcel.2017.10.013 [] [[PubMed]
134. Ortiz-Munoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood. (2014) 124:2625–34. 10.1182/blood-2014-03-562876 ] [
135. Lefrancais E, Mallavia B, Zhuo H, Calfee CS, Looney MR. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight. (2018) 3:98178. 10.1172/jci.insight.98178 ] [
136. Silvestre-Roig C, Hidalgo A, Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood. (2016) 127:2173–81. 10.1182/blood-2016-01-688887 [] [[PubMed]
137. 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) 3:73ra20. 10.1126/scitranslmed.3001201 ] [
138. Lehmann JC, Jablonski-Westrich D, Haubold U, Gutierrez-Ramos JC, Springer T, Hamann A. Overlapping and selective roles of endothelial intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in lymphocyte trafficking. J Immunol. (2003) 171:2588–93. 10.4049/jimmunol.171.5.2588 [] [[PubMed]
139. Woodfin A, Beyrau M, Voisin MB, Ma B, Whiteford JR, Hordijk PL, et al. . ICAM-1-expressing neutrophils exhibit enhanced effector functions in murine models of endotoxemia. Blood. (2016) 127:898–907. 10.1182/blood-2015-08-664995 ] [
140. Ode Y, Aziz M, Wang P. CIRP increases ICAM-1(+) phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis. J Leukoc Biol. (2018) 103:693–707. 10.1002/JLB.3A0817-327RR ] [
141. Alarcon P, Manosalva C, Conejeros I, Carretta MD, Munoz-Caro T, Silva LM R, et al. . d (-) lactic acid-induced adhesion of bovine neutrophils onto endothelial cells is dependent on neutrophils extracellular traps formation and CD11b expression. Front Immunol. (2017) 8:975. 10.3389/fimmu.2017.00975 ] [
142. Folco EJ, Mawson TL, Vromman A, Bernardes-Souza B, Franck G, Persson O, et al. . Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1alpha and cathepsin G. Arterioscler Thromb Vasc Biol. (2018) 38:1901–12. 10.1161/ATVBAHA.118.311150 ] [
143. Elsner J, Sach M, Knopf HP, Norgauer J, Kapp A, Schollmeyer P, et al. . Synthesis and surface expression of ICAM-1 in polymorphonuclear neutrophilic leukocytes in normal subjects and during inflammatory disease. Immunobiology. (1995) 193:456–64. 10.1016/S0171-2985(11)80430-4 [] [[PubMed]
144. Wang SZ, Smith PK, Lovejoy M, Bowden JJ, Alpers JH, Forsyth KD. Shedding of L-selectin and PECAM-1 and upregulation of Mac-1 and ICAM-1 on neutrophils in RSV bronchiolitis. Am J Physiol. (1998) 275:L983–9. 10.1152/ajplung.1998.275.5.L983 [] [[PubMed]
145. Fortunati E, Kazemier KM, Grutters JC, Koenderman L, Van den Boschv J. Human neutrophils switch to an activated phenotype after homing to the lung irrespective of inflammatory disease. Clin Exp Immunol. (2009) 155:559–66. 10.1111/j.1365-2249.2008.03791.x ] [
146. Zhao Y, Yi W, Wan X, Wang J, Tao T, Li J, et al. . Blockade of ICAM-1 improves the outcome of polymicrobial sepsis via modulating neutrophil migration and reversing immunosuppression. Mediators Inflamm. (2014) 2014:195290. 10.1155/2014/195290 ] [
147. Sagiv JY, Voels S, Granot Z. Isolation and characterization of low- vs. high-density neutrophils in cancer. Methods Mol Biol. (2016) 1458:179–93. 10.1007/978-1-4939-3801-8_13 [] [[PubMed]
148. Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types?Front Physiol. (2018) 9:113 10.3389/fphys.2018.00113 ] [
149. Kanamaru R, Ohzawa H, Miyato H, Matsumoto S, Haruta H, Kurashina K, et al. . Low density neutrophils (LDN) in postoperative abdominal cavity assist the peritoneal recurrence through the production of neutrophil extracellular traps (NETs). Sci Rep. (2018) 8:632 10.1038/s41598-017-19091-2 ] [
150. Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, et al. . A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. (2010) 184:3284–97. 10.4049/jimmunol.0902199 ] [
151. Li Y, Li H, Wang H, Pan H, Zhao H, Jin H, et al. . The proportion, origin and pro-inflammation roles of low density neutrophils in SFTS disease. BMC Infect Dis. (2019) 19:109. 10.1186/s12879-019-3701-4 ] [
152. Herteman N, Vargas A, Lavoie JP. Characterization of circulating low-density neutrophils intrinsic properties in healthy and asthmatic horses. Sci Rep. (2017) 7:7743. 10.1038/s41598-017-08089-5 ] [
153. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, et al. . Netting neutrophils induce endothelial damage, infiltrate tissues, expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. (2011) 187:538–52. 10.4049/jimmunol.1100450 ] [
154. Uhl B, Vadlau Y, Zuchtriegel G, Nekolla K, Sharaf K, Gaertner F, et al. . Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. (2016) 128:2327–37. 10.1182/blood-2016-05-718999 ] [
155. Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, et al. . Neutrophil ageing is regulated by the microbiome. Nature. (2015) 525:528–32. 10.1038/nature15367 ] [
156. Ermert D, Urban CF, Laube B, Goosmann C, Zychlinsky A, Brinkmann V. Mouse neutrophil extracellular traps in microbial infections. J Innate Immun. (2009) 1:181–93. 10.1159/000205281 [] [[PubMed]
157. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. (2012) 189:2689–95. 10.4049/jimmunol.1201719 ] [
158. 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) 13:463–9. 10.1038/nm1565 [] [[PubMed]
159. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol Med. (2011) 17:293–307. 10.2119/molmed.2010.00138 ] [
160. Margraf S, Logters T, Reipen J, Altrichter J, Scholz M, Windolf J. Neutrophil-derived circulating free DNA (cf-DNA/NETs): a potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis. Shock. (2008) 30:352–8. 10.1097/SHK.0b013e31816a6bb1 [] [[PubMed]
161. Maruchi Y, Tsuda M, Mori H, Takenaka N, Gocho T, Huq MA, et al. . Plasma myeloperoxidase-conjugated DNA level predicts outcomes and organ dysfunction in patients with septic shock. Crit Care. (2018) 22:176. 10.1186/s13054-018-2109-7 ] [
162. Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, et al. . Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. (2009) 113:6419–27. 10.1182/blood-2008-07-171629 ] [
163. Czaikoski PG, Mota J, Nascimento DC, Sônego F, Castanheira FS, Melo PH, et al. . Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLoS ONE. (2016) 11: e0148142. 10.1371/journal.pone.0148142 ] [
164. Mai SH, Khan M, Dwivedi DJ, Ross CA, Zhou J, Gould TJ, et al Delayed but not early treatment with dnase reduces organ damage and improves outcome in a murine model of sepsis. Shock. (2015) 44:166–72. 10.1097/SHK.0000000000000396 [] [[PubMed][Google Scholar]
165. Patel JM, Sapey E, Parekh D, Scott A, Dosanjh D, Gao F, et al. . Sepsis induces a dysregulated neutrophil phenotype that is associated with increased mortality. Mediators Inflamm. (2018) 2018:4065362. 10.1155/2018/4065362 ] [
166. Hashiba M, Huq A, Tomino A, Hirakawa A, Hattori T, Miyabe H, et al. . Neutrophil extracellular traps in patients with sepsis. J Surg Res. (2015) 194:248–54. 10.1016/j.jss.2014.09.033 [] [[PubMed]
167. Lerman YV, Kim M. Neutrophil Migration under normal and sepsis conditions. Cardiovasc Hematol Disord Drug Targets. (2015) 15:19–28. 10.2174/1871529X15666150108113236 ] [
168. Gupta K, Joshi MB, Philippova M, Erne P, Hasler P, Hahn S, Resink TJ. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett. (2010) 584:3193–7. 10.1016/j.febslet.2010.06.006 [] [[PubMed]
169. Kimball S, Obi AT, Diaz JA, Henke PK. The emerging role of NETs in venous thrombosis and immunothrombosis. Front Immunol. (2016) 7:236. 10.3389/fimmu.2016.00236 ] [
170. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. (2014) 123:2768–76. 10.1182/blood-2013-10-463646 ] [
171. Delabranche X, Stiel L, Severac F, Galoisy AC, Mauvieux L, Zobairi F, et al. . Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock. (2017) 47:313–17. 10.1097/SHK.0000000000000719 [] [[PubMed]
172. McDonald A, Davis RP, Kim SJ, Tse M, Esmon CT, Kolaczkowska E, et al. . Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood. (2017) 129:1357–67. 10.1182/blood-2016-09-741298 ] [
173. Yang S, Qi H, Kan K, Chen J, Xie H, Guo X, et al. . Neutrophil extracellular traps promote hypercoagulability in patients with sepsis. Shock. (2017) 47:132–9. 10.1097/SHK.0000000000000741 [] [[PubMed]
174. Mikacenic A, Moore R, Dmyterko V, West TE, Altemeier WA, Liles WC, et al. . Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia. Crit Care. (2018) 22:358. 10.1186/s13054-018-2290-8 ] [
175. Li RH L, Johnson LR, Kohen C, Tablin F. A novel approach to identifying and quantifying neutrophil extracellular trap formation in septic dogs using immunofluorescence microscopy. BMC Vet Res. (2018) 14:210. 10.1186/s12917-018-1523-z ] [
176. Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, et al. . Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB J. (2013) 27:5010–21. 10.1096/fj.13-236380 ] [
177. Peterson MW, Walter ME, Nygaard SD. Effect of neutrophil mediators on epithelial permeability. Am J Respir Cell Mol Biol. (1995) 13:719–27. 10.1165/ajrcmb.13.6.7576710 [] [[PubMed]
178. Ishii T, Doi K, Okamoto K, Imamura M, Dohi M, Yamamoto K, et al. . Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy. Am J Pathol. (2010) 177:1665–73. 10.2353/ajpath.2010.090793 ] [
179. Tsai YF, Yu HP, Chang WY, Liu FC, Huang ZC, Hwang TL. Sirtinol inhibits neutrophil elastase activity and attenuates lipopolysaccharide-mediated acute lung injury in mice. Sci Rep. (2015) 5:8347. 10.1038/srep08347 ] [
180. Biron BM, Chung CS, O'Brien XM, Chen Y, Reichner JS, Ayala A. Cl-amidine prevents histone 3 citrullination, net formation, and improves survival in a murine sepsis model. J Innate Immun. (2017) 9:22–32. 10.1159/000448808 ] [
181. Boone BA, Murthy P, Miller-Ocuin J, Doerfler WR, Ellis JT, Liang X, et al. . Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. BMC Cancer. (2018) 18:678. 10.1186/s12885-018-4584-2 ] [
182. Healy LD, Puy C, Fernandez JA, Mitrugno A, Keshari RS, Taku NA, et al. . Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem. (2017) 292:8616–29. 10.1074/jbc.M116.768309 ] [
183. Alaniz C. An update on activated protein C (Xigris) in the management of sepsis. P T. (2010) 35:504–8, 29.
184. Marti-Carvajal J, Sola I, Gluud C, Lathyris D, Cardona AF. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev. (2012) 12:Cd004388. 10.1002/14651858.CD004388.pub6 ] [
185. Li Y, Liu Z, Liu B, Zhao T, Chong W, Wang Y, et al. . Citrullinated histone H3 – a novel target for treatment of sepsis. Surgery. (2014) 156:229–34. 10.1016/j.surg.2014.04.009 ] [
186. Yokoyama Y, Ito T, Yasuda T, Furubeppu H, Kamikokuryo C, Yamada S, et al. . Circulating histone H3 levels in septic patients are associated with coagulopathy, multiple organ failure, and death: a single-center observational study. Thromb J. (2019) 17:1. 10.1186/s12959-018-0190-4 ] [
187. 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) 125:1948–56. 10.1182/blood-2014-07-587709 ] [[Google Scholar]
188. Biron BM, Chung CS, Chen Y, Wilson Z, Fallon EA, Reichner JS, et al. . PAD4 deficiency leads to decreased organ dysfunction and improved survival in a dual insult model of hemorrhagic shock and sepsis. J Immunol. (2018) 200:1817–28. 10.4049/jimmunol.1700639 ] [
189. Lewis HD, Liddle J, Coote JE, Atkinson SJ, Barker MD, Bax BD, et al. . Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol. (2015) 11:189–91. 10.1038/nchembio.1735 ] [
190. Tadie JM, Bae HB, Jiang S, Park DW, Bell CP, Yang H, et al. . HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am J Physiol Lung Cell Mol Physiol. (2013) 304:L342–9. 10.1152/ajplung.00151.2012 ] [
191. Liu L, Mao Y, Xu B, Zhang X, Fang C, Ma Y, et al. . Induction of neutrophil extracellular traps during tissue injury: involvement of STING and Toll-like receptor 9 pathways. Cell Prolif . (2019) 52:e12579. 10.1111/cpr.12579 ] [
192. Al-Banna N, Lehmann C. Oxidized LDL and LOX-1 in experimental sepsis. Mediators Inflamm. (2013) 2013:761789. 10.1155/2013/761789 ] [
193. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. . Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. (2011) 108:235–48. 10.1161/CIRCRESAHA.110.223875 ] [
194. Awasthi A, Nagarkoti S, Kumar A, Dubey M, Singh AK, Pathak P, et al. . Oxidized LDL induced extracellular trap formation in human neutrophils via TLR-PKC-IRAK-MAPK and NADPH-oxidase activation. Free Radic Biol Med. (2016) 93:190–203. 10.1016/j.freeradbiomed.2016.01.004 [] [[PubMed]
195. Boe DM, Curtis BJ, Chen MM, Ippolito JA, Kovacs EJ. Extracellular traps and macrophages: new roles for the versatile phagocyte. J Leukoc Biol. (2015) 97:1023–35. 10.1189/jlb.4RI1014-521R ] [
196. Ueki S, Tokunaga T, Fujieda S, Honda K, Hirokawa M, Spencer LA, et al. . Eosinophil ETosis and DNA Traps: a New Look at Eosinophilic Inflammation. Curr Allergy Asthma Rep. (2016) 16:54. 10.1007/s11882-016-0634-5 ] [