Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin coated with histones, proteases and granular and cytosolic proteins that help catch and kill microorganisms
Kupffer cells and neutrophils in the liver cooperate to eliminate pathogens in circulation
NETs have a potential role in gastrointestinal infection and sepsis, whereas several pathogenic bacteria are capable of escaping or hijacking NET-mediated capturing and killing
Excess NET formation is associated with the pathology of inflammatory liver and gastrointestinal diseases
Exposure to components of NETs might generate autoantibodies in gastrointestinal autoimmune diseases and facilitate the inappropriate immune response
Therapies that target key pathways in NET formation, with or without other treatments, might improve the treatment for gastrointestinal inflammatory diseases, cancer and thrombosis
Neutrophil extracellular traps (NETs) have an important role during infection by helping neutrophils to capture and kill pathogens. However, evidence is accumulating that uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. In this Review, we focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects. The latest mechanistic insights in NET formation, interactions between microorganisms and NETs and the relationship between neutrophil subtypes and their functions are also discussed. Additionally, we describe the potential importance of NET-related molecules, including cell-free DNA and hypercitrullinated histones, as biomarkers and targets for therapeutic intervention in gastrointestinal diseases.
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Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).
Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).
Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13, 463–469 (2007).
Pilsczek, F. H. et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J. Immunol. 185, 7413–7425 (2010).
Bianchi, M. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 114, 2619–2622 (2009).
Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med. 23, 279–287 (2017).
Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).
Wong, S. L. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 21, 815–819 (2015).
Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).
Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).
Bennike, T. B. et al. Neutrophil extracellular traps in ulcerative colitis: a proteome analysis of intestinal biopsies. Inflamm. Bowel Dis. 21, 2052–2067 (2015).
Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).
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. 59, 229–240 (1996).
Urban, C. F. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 5, e1000639 (2009).
Jaillon, S. et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J. Exp. Med. 204, 793–804 (2007).
Fuchs, T. A. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176, 231–241 (2007).
Kobayashi, S. D. & DeLeo, F. R. Role of neutrophils in innate immunity: a systems biology-level approach. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 309–333 (2009).
Gupta, A. K., Giaglis, S., Hasler, P. & Hahn, S. Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A. PLoS ONE 9, e97088 (2014).
Hakkim, A. et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat. Chem. Biol. 7, 75–77 (2011).
Van Avondt, K., van der Linden, M., Naccache, P. H., Egan, D. A. & Meyaard, L. Signal inhibitory receptor on leukocytes-1 limits the formation of neutrophil extracellular traps, but preserves intracellular bacterial killing. J. Immunol. 196, 3686–3694 (2016).
Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).
Palmer, L. J. et al. Hypochlorous acid regulates neutrophil extracellular trap release in humans. Clin. Exp. Immunol. 167, 261–268 (2012).
Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A. & Papayannopoulos, V. A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Rep. 8, 883–896 (2014).
Papayannopoulos, V., Metzler, K. D., Hakkim, A. & Zychlinsky, A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191, 677–691 (2010).
Amulic, B. et al. Cell-cycle proteins control production of neutrophil extracellular traps. Dev. Cell 43, 449–462.e5 (2017).
Remijsen, Q. et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21, 290–304 (2011).
Desai, J., Mulay, S. R., Nakazawa, D. & Anders, H. J. Matters of life and death. How neutrophils die or survive along NET release and is “NETosis” = necroptosis? Cell. Mol. Life Sci. 73, 2211–2219 (2016).
Yipp, B. G. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat. Med. 18, 1386–1393 (2012).
Yipp, B. G. & Kubes, P. NETosis: how vital is it? Blood 122, 2784–2794 (2013).
Byrd, A. S., O'Brien, X. M., Johnson, C. M., Lavigne, L. M. & Reichner, J. S. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. J. Immunol. 190, 4136–4148 (2013).
McDonald, B., Urrutia, R., Yipp, B. G., Jenne, C. N. & Kubes, P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12, 324–333 (2012).
Deppermann, C. & Kubes, P. Platelets and infection. Semin. Immunol. 28, 536–545 (2016).
Rochael, N. C. et al. Classical ROS-dependent and early/rapid ROS-independent release of neutrophil extracellular traps triggered by Leishmania parasites. Sci. Rep. 5, 18302 (2015).
Leppkes, M. et al. Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat. Commun. 7, 10973 (2016).
Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I. & Simon, H. U. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 16, 1438–1444 (2009).
Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 14, 949–953 (2008).
Konig, M. F. & Andrade, F. A. Critical reappraisal of neutrophil extracellular traps and NETosis mimics based on differential requirements for protein citrullination. Front. Immunol. 7, 461 (2016).
Hoppenbrouwers, T. et al. In vitro induction of NETosis: comprehensive live imaging comparison and systematic review. PLoS ONE 12, e0176472 (2017).
Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).
Marques, P. E. et al. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology 61, 348–360 (2015).
Nauseef, W. M. & Kubes, P. Pondering neutrophil extracellular traps with healthy skepticism. Cell. Microbiol. 18, 1349–1357 (2016).
Belorgey, D. & Bieth, J. G. Effect of polynucleotides on the inhibition of neutrophil elastase by mucus proteinase inhibitor and alpha 1-proteinase inhibitor. Biochemistry 37, 16416–16422 (1998).
Kolaczkowska, E. et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat. Commun. 6, 6673 (2015).
Yan, J., Li, S. & Li, S. The role of the liver in sepsis. Int. Rev. Immunol. 33, 498–510 (2014).
McDonald, B. & Kubes, P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol. Pathol. 40, 157–165 (2012).
Surewaard, B. G. et al. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J. Exp. Med. 213, 1141–1151 (2016).
David, B. A. et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151, 1176–1191 (2016).
Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).
Helmy, K. Y. et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915–927 (2006).
Holers, V. M. Complement and its receptors: new insights into human disease. Annu. Rev. Immunol. 32, 433–459 (2014).
Zeng, Z. et al. CRIg functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne Gram-positive bacteria. Cell Host Microbe 20, 99–106 (2016).
Ravetch, J. V. & Bolland, S. IgG Fc receptors. Annu. Rev. Immunol. 19, 275–290 (2001).
Wong, C. H., Jenne, C. N., Petri, B., Chrobok, N. L. & Kubes, P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat. Immunol. 14, 785–792 (2013).
Bleriot, C. et al. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42, 145–158 (2015).
McDonald, B., Jenne, C. N., Zhuo, L., Kimata, K. & Kubes, P. Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G797–806 (2013).
Jenne, C. N. et al. Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe 13, 169–180 (2013).
Saitoh, T. et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe 12, 109–116 (2012).
Ward, C. M., Tetaz, T. J., Andrews, R. K. & Berndt, M. C. Binding of the von Willebrand factor A1 domain to histone. Thromb. Res. 86, 469–477 (1997).
Averhoff, P., Kolbe, M., Zychlinsky, A. & Weinrauch, Y. Single residue determines the specificity of neutrophil elastase for Shigella virulence factors. J. Mol. Biol. 377, 1053–1066 (2008).
Buchanan, J. T. et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 16, 396–400 (2006).
Derre-Bobillot, A. et al. Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence. Mol. Microbiol. 89, 518–531 (2013).
Mollerherm, H. et al. Yersinia enterocolitica-mediated degradation of neutrophil extracellular traps (NETs). FEMS Microbiol. Lett. 362, fnv192 (2015).
Carestia, A. et al. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J. Leukoc. Biol. 99, 153–162 (2016).
Khoruts, A. & Sadowsky, M. J. Understanding the mechanisms of faecal microbiota transplantation. Nat. Rev. Gastroenterol. Hepatol. 13, 508–516 (2016).
Seper, A. et al. Vibrio cholerae evades neutrophil extracellular traps by the activity of two extracellular nucleases. PLoS Pathog. 9, e1003614 (2013).
Juneau, R. A., Stevens, J. S., Apicella, M. A. & Criss, A. K. A thermonuclease of Neisseria gonorrhoeae enhances bacterial escape from killing by neutrophil extracellular traps. J. Infect. Dis. 212, 316–324 (2015).
Abi Abdallah, D. S. et al. Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps. Infect. Immun. 80, 768–777 (2012).
Konstantinidis, T. et al. Immunomodulatory role of clarithromycin in Acinetobacter baumannii infection via formation of neutrophil extracellular traps. Antimicrob. Agents Chemother. 60, 1040–1048 (2016).
Brogden, G. et al. beta-Glucan protects neutrophil extracellular traps against degradation by Aeromonas hydrophila in carp (Cyprinus carpio). Fish Shellfish Immunol. 33, 1060–1064 (2012).
Bruns, S. et al. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA. PLoS Pathog. 6, e1000873 (2010).
Marin-Esteban, V. et al. Afa/Dr diffusely adhering Escherichia coli strain C1845 induces neutrophil extracellular traps that kill bacteria and damage human enterocyte-like cells. Infect. Immun. 80, 1891–1899 (2012).
Crane, J. K., Broome, J. E. & Lis, A. Biological activities of uric acid in infection due to enteropathogenic and Shiga-toxigenic Escherichia coli. Infect. Immun. 84, 976–988 (2016).
Berends, E. T. et al. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J. Innate Immun. 2, 576–586 (2010).
Liechti, G. W. & Goldberg, J. B. Helicobacter pylori salvages purines from extracellular host cell DNA utilizing the outer membrane-associated nuclease NucT. J. Bacteriol. 195, 4387–4398 (2013).
Schilcher, K. et al. Increased neutrophil extracellular trap-mediated Staphylococcus aureus clearance through inhibition of nuclease activity by clindamycin and immunoglobulin. J. Infect. Dis. 210, 473–482 (2014).
Neumann, A. et al. Novel role of the antimicrobial peptide LL-37 in the protection of neutrophil extracellular traps against degradation by bacterial nucleases. J. Innate Immun. 6, 860–868 (2014).
Saha, P. et al. Bacterial siderophores hijack neutrophil functions. J. Immunol. 198, 4293–4303 (2017).
Halverson, T. W., Wilton, M., Poon, K. K., Petri, B. & Lewenza, S. DNA is an antimicrobial component of neutrophil extracellular traps. PLoS Pathog. 11, e1004593 (2015).
Kalliomaki, M., Salminen, S., Poussa, T., Arvilommi, H. & Isolauri, E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 361, 1869–1871 (2003).
Yan, F. et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132, 562–575 (2007).
Vong, L., Lorentz, R. J., Assa, A., Glogauer, M. & Sherman, P. M. Probiotic Lactobacillus rhamnosus inhibits the formation of neutrophil extracellular traps. J. Immunol. 192, 1870–1877 (2014).
Vong, L. et al. Selective enrichment of commensal gut bacteria protects against Citrobacter rodentium-induced colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G181–G192 (2015).
Vong, L., Yeung, C. W., Pinnell, L. J. & Sherman, P. M. Adherent-invasive Escherichia coli exacerbates antibiotic-associated intestinal dysbiosis and neutrophil extracellular trap activation. Inflamm. Bowel Dis. 22, 42–54 (2016).
Dicker, A. J. et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. http://dx.doi.org/10.1016/j.jaci.2017.04.022 (2017).
Kubes, P. & Mehal, W. Z. Sterile inflammation in the liver. Gastroenterology 143, 1158–1172 (2012).
Lowe, P. P. et al. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. PLoS ONE 12, e0174544 (2017).
Rensen, S. S. et al. Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice. PLoS ONE 7, e52411 (2012).
Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).
Mansuy-Aubert, V. et al. Imbalance between neutrophil elastase and its inhibitor alpha1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab. 17, 534–548 (2013).
Merza, M. et al. Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology 149, 1920–1931.e8 (2015).
Bilyy, R. et al. Neutrophil extracellular traps form a barrier between necrotic and viable areas in acute abdominal inflammation. Front. Immunol. 7, 424 (2016).
Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).
Tanaka, K. et al. In vivo characterization of neutrophil extracellular traps in various organs of a murine sepsis model. PLoS ONE 9, e111888 (2014).
Fattahi, F. et al. Organ distribution of histones after intravenous infusion of FITC histones or after sepsis. Immunol. Res. 61, 177–186 (2015).
Dwivedi, D. J. et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit. Care 16, R151 (2012).
Hampson, P. et al. Neutrophil dysfunction, immature granulocytes, and cell-free DNA are early biomarkers of sepsis in burn-injured patients: a prospective observational cohort study. Ann. Surg. 265, 1241–1249 (2017).
Hirsch, J. G. Bactericidal action of histone. J. Exp. Med. 108, 925–944 (1958).
Saffarzadeh, M. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS ONE 7, e32366 (2012).
Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15, 1318–1321 (2009).
Czaikoski, P. G. et al. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLoS ONE 11, e0148142 (2016).
McDonald, B. et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 129, 1357–1367 (2017).
Martinod, K. et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood 125, 1948–1956 (2015).
Meng, W. et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit. Care 16, R137 (2012).
Derikx, J. P., Poeze, M., van Bijnen, A. A., Buurman, W. A. & Heineman, E. Evidence for intestinal and liver epithelial cell injury in the early phase of sepsis. Shock 28, 544–548 (2007).
Gao, X. et al. Neutrophil extracellular traps contribute to the intestine damage in endotoxemic rats. J. Surg. Res. 195, 211–218 (2015).
Kimball, A. S., Obi, A. T., Diaz, J. A. & Henke, P. K. The emerging role of NETs in venous thrombosis and immunothrombosis. Front. Immunol. 7, 236 (2016).
Gould, T. J. et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler. Thromb. Vasc. Biol. 34, 1977–1984 (2014).
Ammollo, C. T., Semeraro, F., Xu, J., Esmon, N. L. & Esmon, C. T. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J. Thromb. Haemost. 9, 1795–1803 (2011).
Demers, M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc. Natl Acad. Sci. USA 109, 13076–13081 (2012).
Demers, M. & Wagner, D. D. Neutrophil extracellular traps: a new link to cancer-associated thrombosis and potential implications for tumor progression. Oncoimmunology 2, e22946 (2013).
Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).
Semeraro, F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118, 1952–1961 (2011).
Alazawi, W., Pirmadjid, N., Lahiri, R. & Bhattacharya, S. Inflammatory and immune responses to surgery and their clinical impact. Ann. Surg. 264, 73–80 (2016).
Lord, J. M. et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet 384, 1455–1465 (2014).
Itagaki, K. et al. Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS ONE 10, e0120549 (2015).
Slaba, I. et al. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice. Hepatology 62, 1593–1605 (2015).
Honda, M. et al. Intravital imaging of neutrophil recruitment reveals the efficacy of FPR1 blockade in hepatic ischemia-reperfusion injury. J. Immunol. 198, 1718–1728 (2017).
Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion — from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).
Zhai, Y., Petrowsky, H., Hong, J. C., Busuttil, R. W. & Kupiec-Weglinski, J. W. Ischaemia-reperfusion injury in liver transplantation — from bench to bedside. Nat. Rev. Gastroenterol. Hepatol. 10, 79–89 (2013).
Oklu, R., Albadawi, H., Jones, J. E., Yoo, H. J. & Watkins, M. T. Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps. J. Vasc. Surg. 58, 1627–1636 (2013).
Albadawi, H. et al. Effect of DNase I treatment and neutrophil depletion on acute limb ischemia-reperfusion injury in mice. J. Vasc. Surg. 64, 484–493 (2016).
Savchenko, A. S. et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123, 141–148 (2014).
Ge, L. et al. Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am. J. Physiol. Heart Circ. Physiol. 308, H500–509 (2015).
Huang, H. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62, 600–614 (2015).
Al-Khafaji, A. B. et al. Superoxide induces neutrophil extracellular trap formation in a TLR-4 and NOX-dependent mechanism. Mol. Med. 22, 621–631 (2016).
Nakazawa, D. et al. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J. Am. Soc. Nephrol. 28, 1753–1768 (2017).
Carter, M. B., Wilson, M. A., Wead, W. B. & Garrison, R. N. Pulmonary subpleural arteriolar diameters during intestinal ischemia/reperfusion. J. Surg. Res. 59, 51–58 (1995).
Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).
Rosenberg, L. et al. Histologic markers of inflammation in patients with ulcerative colitis in clinical remission. Clin. Gastroenterol. Hepatol. 11, 991–996 (2013).
de Souza, H. S. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13–27 (2016).
Uchiyama, K. et al. Serpin B1 protects colonic epithelial cell via blockage of neutrophil elastase activity and its expression is enhanced in patients with ulcerative colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1163–G1170 (2012).
Kato, S. et al. Increased expression of long pentraxin PTX3 in inflammatory bowel diseases. Dig. Dis. Sci. 53, 1910–1916 (2008).
Darrah, E. & Andrade, F. NETs: the missing link between cell death and systemic autoimmune diseases? Front. Immunol. 3, 428 (2012).
He, Z. et al. Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease. Thromb. Haemost. 115, 738–751 (2016).
Zhou, G. et al. CD177+ neutrophils as functionally activated neutrophils negatively regulate IBD. Gut http://dx.doi.org/10.1136/gutjnl-2016-313535 (2017).
Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).
Ruemmele, F. M. et al. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology 115, 822–829 (1998).
Zhou, G. et al. ASCA, ANCA, ALCA and many more: are they useful in the diagnosis of inflammatory bowel disease? Dig. Dis. 34, 90–97 (2016).
Jarrot, P. A. & Kaplanski, G. Pathogenesis of ANCA-associated vasculitis: an update. Autoimmun. Rev. 15, 704–713 (2016).
Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15, 623–625 (2009).
Sangaletti, S. et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 120, 3007–3018 (2012).
Sugi, K. et al. Antineutrophil cytoplasmic antibodies in Japanese patients with inflammatory bowel disease: prevalence and recognition of putative antigens. Am. J. Gastroenterol. 94, 1304–1312 (1999).
Mahler, M. et al. PR3-ANCA: a promising biomarker for ulcerative colitis with extensive disease. Clin. Chim. Acta 424, 267–273 (2013).
Mieli-Vergani, G. & Vergani, D. Autoimmune hepatitis. Nat. Rev. Gastroenterol. Hepatol. 8, 320–329 (2011).
Burlingame, R. W., Rubin, R. L. & Rosenberg, A. M. Autoantibodies to chromatin components in juvenile rheumatoid arthritis. Arthritis Rheum. 36, 836–841 (1993).
Czaja, A. J., Nishioka, M., Morshed, S. A. & Hachiya, T. Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. Gastroenterology 107, 200–207 (1994).
Selmi, C., Bowlus, C. L., Gershwin, M. E. & Coppel, R. L. Primary biliary cirrhosis. Lancet 377, 1600–1609 (2011).
Kaplan, M. M. & Gershwin, M. E. Primary biliary cirrhosis. N. Engl. J. Med. 353, 1261–1273 (2005).
Bambha, K. et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 125, 1364–1369 (2003).
Mendes, F. & Lindor, K. D. Primary sclerosing cholangitis: overview and update. Nat. Rev. Gastroenterol. Hepatol. 7, 611–619 (2010).
Stinton, L. M. et al. PR3-ANCA: a promising biomarker in primary sclerosing cholangitis (PSC). PLoS ONE 9, e112877 (2014).
Kerkar, N. et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 351, 409–413 (1998).
Kerkar, N. & Yanni, G. 'De novo' and 'recurrent' autoimmune hepatitis after liver transplantation: a comprehensive review. J. Autoimmun. 66, 17–24 (2016).
Dubel, L., Farges, O., Johanet, C., Sebagh, M. & Bismuth, H. High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection. Transplantation 65, 1072–1075 (1998).
Eksteen, B., Afford, S. C., Wigmore, S. J., Holt, A. P. & Adams, D. H. Immune-mediated liver injury. Semin. Liver Dis. 27, 351–366 (2007).
Mano, Y. et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann. Surg. 258, 301–305 (2013).
Asaoka, T. et al. Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer. Pancreatology 16, 434–440 (2016).
Malik, H. Z. et al. Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases. Ann. Surg. 246, 806–814 (2007).
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
Fridlender, Z. G. & Albelda, S. M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).
Hubert, P. et al. Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. Cancer Res. 71, 5134–5143 (2011).
van Gisbergen, K. P., Geijtenbeek, T. B. & van Kooyk, Y. Close encounters of neutrophils and DCs. Trends Immunol. 26, 626–631 (2005).
Beauvillain, C. et al. Neutrophils efficiently cross-prime naive T cells in vivo. Blood 110, 2965–2973 (2007).
Jablonska, J., Leschner, S., Westphal, K., Lienenklaus, S. & Weiss, S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Invest. 120, 1151–1164 (2010).
Gabrilovich, D. I. et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 67, 425–426. (2007).
Brandau, S., Moses, K. & Lang, S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin. Cancer Biol. 23, 171–182 (2013).
Moses, K. & Brandau, S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin. Immunol. 28, 187–196 (2016).
Toor, S. M. et al. Increased levels of circulating and tumor-infiltrating granulocytic myeloid cells in colorectal cancer patients. Front. Immunol. 7, 560 (2016).
Kalathil, S., Lugade, A. A., Miller, A., Iyer, R. & Thanavala, Y. Higher frequencies of GARP+CTLA-4+Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 73, 2435–2444 (2013).
Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).
Millrud, C. R. et al. NET-producing CD16high CD62Ldim neutrophils migrate to tumor sites and predict improved survival in patients with HNSCC. Int. J. Cancer 140, 2557–2567 (2017).
Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).
Pieterse, E. et al. Neutrophil extracellular traps drive endothelial-to-mesenchymal transition. Arterioscler. Thromb. Vasc. Biol. 37, 1371–1379 (2017).
Najmeh, S. et al. Neutrophil extracellular traps sequester circulating tumor cells via beta1-integrin mediated interactions. Int. J. Cancer 140, 2321–2330 (2017).
Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl Med. 8, 361ra138 (2016).
Guglietta, S. & Rescigno, M. Hypercoagulation and complement: connected players in tumor development and metastases. Semin. Immunol. 28, 578–586 (2016).
Boone, B. A. et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther. 22, 326–334 (2015).
Yang, C. et al. Procoagulant role of neutrophil extracellular traps in patients with gastric cancer. Int. J. Clin. Exp. Pathol. 8, 14075–14086 (2015).
Arelaki, S. et al. Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth. PLoS ONE 11, e0154484 (2016).
Guglietta, S. et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat. Commun. 7, 11037 (2016).
Barkin, J. S. & Goldstein, J. A. Diagnostic and therapeutic approach to pancreatic cancer. Biomed. Pharmacother. 54, 400–409 (2000).
Wen, F., Shen, A., Choi, A., Gerner, E. W. & Shi, J. Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis. Cancer Res. 73, 4256–4266 (2013).
Abdol Razak, N., Elaskalani, O. & Metharom, P. Pancreatic cancer-induced neutrophil extracellular traps: a potential contributor to cancer-associated thrombosis. Int. J. Mol. Sci. 18, 487 (2017).
Hecht, S. S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat. Rev. Cancer 3, 733–744 (2003).
Hosseinzadeh, A., Thompson, P. R., Segal, B. H. & Urban, C. F. Nicotine induces neutrophil extracellular traps. J. Leukoc. Biol. 100, 1105–1112 (2016).
Donnellan, E., Kevane, B., Bird, B. R. & Ainle, F. N. Cancer and venous thromboembolic disease: from molecular mechanisms to clinical management. Curr. Oncol. 21, 134–143 (2014).
Blom, J. W., Doggen, C. J., Osanto, S. & Rosendaal, F. R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293, 715–722 (2005).
Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).
von Bruhl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).
Kambas, K. et al. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Ann. Rheum. Dis. 73, 1854–1863 (2014).
Cedervall, J. et al. Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 75, 2653–2662 (2015).
Thomson, A. H. Human recombinant DNase in cystic fibrosis. J. R. Soc. Med. 88 (Suppl. 25), 24–29 (1995).
Sayah, D. M. et al. Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation. Am. J. Respir. Crit. Care Med. 191, 455–463 (2015).
Macanovic, M. et al. The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243–252 (1996).
Davis, J. C. Jr et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68–76 (1999).
Neeli, I., Dwivedi, N., Khan, S. & Radic, M. Regulation of extracellular chromatin release from neutrophils. J. Innate Immun. 1, 194–201 (2009).
Bjornsdottir, H. et al. Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species. Free Radic. Biol. Med. 89, 1024–1035 (2015).
Campbell, A. M., Kashgarian, M. & Shlomchik, M. J. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci. Transl Med. 4, 157ra141 (2012).
Maicas, N. et al. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid. Redox Signal 15, 889–901 (2011).
Winkelstein, J. A. et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine 79, 155–169 (2000).
Lai, Z. W. et al. N-Acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937–2946 (2012).
Stravitz, R. T. et al. Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival. Liver Int. 33, 1324–1331 (2013).
D'Amico, F. et al. Use of N-acetylcysteine during liver procurement: a prospective randomized controlled study. Liver Transpl. 19, 135–144 (2013).
Orban, J. C. et al. Effect of N-acetylcysteine pretreatment of deceased organ donors on renal allograft function: a randomized controlled trial. Transplantation 99, 746–753 (2015).
Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra140 (2013).
Taylor, P. C. & Feldmann, M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat. Rev. Rheumatol 5, 578–582 (2009).
Kunwar, S., Dahal, K. & Sharma, S. Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int. 36, 1065–1075 (2016).
Danese, S., Vuitton, L. & Peyrin-Biroulet, L. Biologic agents for IBD: practical insights. Nat. Rev. Gastroenterol. Hepatol. 12, 537–545 (2015).
Wang, Y. et al. Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc. Natl Acad. Sci. USA 93, 8563–8568 (1996).
Jayne, D. R. et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J. Am. Soc. Nephrol. 28, 2756–2767 (2017).
Meier-Kriesche, H. U. et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am. J. Transplant. 6, 1111–1131 (2006).
Zavada, J. et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus 19, 1281–1289 (2010).
Lee, Y. H., Lee, H. S., Choi, S. J., Dai Ji, J. & Song, G. G. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus 20, 636–640 (2011).
Zheng, W. et al. PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. J. Pharmacol. Exp. Ther. 353, 288–298 (2015).
Knight, J. S. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. Clin. Invest. 123, 2981–2993 (2013).
Tsuda, Y. et al. Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21, 215–226 (2004).
Denny, M. F. 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. 184, 3284–3297 (2010).
Clemmensen, S. N. et al. Olfactomedin 4 defines a subset of human neutrophils. J. Leukoc. Biol. 91, 495–500 (2012).
Welin, A. et al. The human neutrophil subsets defined by the presence or absence of OLFM4 both transmigrate into tissue in vivo and give rise to distinct NETs in vitro. PLoS ONE 8, e69575 (2013).
Christoffersson, G. et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 120, 4653–4662 (2012).
Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).
The authors thank Servier for providing Servier Medical Art, which was used for creation of original figures. The work in the authors' laboratories is supported by grants from the Canadian Institutes of Health Research, Alberta Innovates Health Solutions, the Heart and Stroke Foundation of Canada and the Canada Research Chairs programme.
The authors declare no competing financial interests.
A structure in the eukaryotic cell nucleus that contains primarily DNA and nuclear proteins such as histones.
Unprogrammed death of cells and living tissue induced by external or internal factors.
- Neutrophil elastase
A serine protease secreted by neutrophils during inflammation.
The most abundant protein of neutrophils; catalyses the conversion of H2O2 and chloride into hypochlorous acid.
- NADPH oxidase complex
A membrane-bound enzyme complex that produces reactive oxygen species when activated.
The hyperactive conversion of arginine to citrulline.
The movement of organisms responding to chemical stimuli.
The process by which phagocytes ingest or engulf other cells or particles.
The specific process for the autophagic elimination of damaged mitochondria.
The introduction of a segment of DNA or RNA into a eukaryotic cell by use of various physical or chemical methods or through viral infection.
- Kupffer cells
Self-sustaining, liver-resident macrophages found in the liver sinusoids.
- Liver sinusoids
Sinusoidal blood vessels that are lined with endothelial cells and that receive blood from terminal branches of the hepatic artery and portal vein and deliver it into central veins.
- Complement receptor of immunoglobulin superfamily
A macrophage complement receptor that recognizes the activated form of complement C3, which opsonizes pathogens, apoptotic cells and foreign antigens.
- von Willebrand factor
A large multimeric glycoprotein circulating in blood plasma that binds coagulation factor VIII and platelets and that mediates platelet adhesion to collagen at sites of vascular injury.
- Damage-associated molecular patterns
Host biomolecules released by cellular injury that act as endogenous danger signals to activate the inflammatory response.
- Cytokine storm
Uncontrolled excessive cytokine release that leads to detrimental effects, including leakage from capillaries, tissue oedema, organ failure and shock.
- Anti-neutrophil cytoplasmic autoantibodies
Autoantibodies that bind to enzymes from neutrophil cytoplasmic granules and are biomarkers for a number of autoimmune diseases.
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Honda, M., Kubes, P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol 15, 206–221 (2018). https://doi.org/10.1038/nrgastro.2017.183
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