Extracellular neutrophil traps (NETs) in the pathogenesis of thrombosis and thromboinflammation
- Authors: Bitsadze V.O.1, Slukhanchuk E.V.2, Khizroeva J.H.1, Tretyakova M.V.3,4, Shkoda A.S.5, Radetskaya L.S.1, Makatsariya A.D.1, Elalamy I.6,7, Gris J.1,8, Grandone E.9,10
-
Affiliations:
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
- Petrovsky National Research Center of Surgery
- The First I.M. Sechenov Moscow State Medical University (Sechenov University)
- Medical Center LLC
- L.A. Vorokhobov City Clinical Hospital Sixty-seven
- I.M. Sechenov Moscow State Medical University (Sechenov University)
- Medicine Sorbonne University, University Hospital Tenon
- University Montpellier, France
- The First I.M. Sechenov Moscow State Medical University, (Sechenov University)
- Thrombosis and Haemostasis Research Unit, Fondazione I.R.C.C.S. "Casa Sollievo della Sofferenza"
- Issue: Vol 76, No 1 (2021)
- Pages: 75-85
- Section: CARDIOLOGY AND CARDIOVASCULAR SURGERY: CURRENT ISSUES
- URL: https://journals.rcsi.science/vramn/article/view/125714
- DOI: https://doi.org/10.15690/vramn1395
- ID: 125714
Cite item
Full Text
Abstract
This article summarizes numerous studies on the relationship of biological processes such as inflammation and thrombosis. The huge role of neutrophils and the extracellular neutrophil traps (NETs) secreted by them has been demonstrated. The discovery of NETs has opened new horizons in the understanding of neutrophil biology and the role of these cells in the body. The use of chromatin in combination with the intracellular proteins, as an effective antimicrobial agent has ancient roots and changes our understanding of chromatin only as a carrier of genetic information. Through NETs, neutrophils can contribute to the development of pathological venous and arterial thrombosis or “immunothrombosis”, as well as atherosclerosis. NETs release has been shown to be one of the causes of thrombosis in conditions such as sepsis and cancer. The presence of NETs in these diseases and conditions makes it possible to use them or individual components as potential biomarkers. NETs and their components may be attractive as therapeutic targets. Further studies of neutrophils and NETs are needed to develop new approaches to the diagnosis and treatment of inflammatory and thrombotic conditions. Perhaps long-forgotten drugs will find a new area for effective use.
Full Text
##article.viewOnOriginalSite##About the authors
Victoria O. Bitsadze
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: vikabits@mail.ru
ORCID iD: 0000-0001-8404-1042
SPIN-code: 5930-0859
MD, PhD, Professor
Russian Federation, 8-2, Trubetskaya street, Moscow, 119992Ekaterina V. Slukhanchuk
Petrovsky National Research Center of Surgery
Email: beloborodova@rambler.ru
ORCID iD: 0000-0001-7441-2778
SPIN-code: 7423-8944
MD, PhD, Assistant Professor
Russian Federation, 2, Abrikosovsky pereulok, Moscow, 119991Jamilya H. Khizroeva
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: jamatotu@gmail.com
ORCID iD: 0000-0002-0725-9686
SPIN-code: 8225-4976
Scopus Author ID: 57194547147
ResearcherId: F-8384-2017
MD, PhD, Professor
Russian Federation, 8-2, Trubetskaya street, Moscow, 119992Maria V. Tretyakova
The First I.M. Sechenov Moscow State Medical University (Sechenov University); Medical Center LLC
Email: tretyakova777@yandex.ru
ORCID iD: 0000-0002-3628-0804
SPIN-code: 1463-0065
MD, PhD, Assistant Professor
Russian Federation, 8-2, Trubetskaya street, Moscow, 119992; Timura Frunze str.15/1, 119021, MoscowAndrei S. Shkoda
L.A. Vorokhobov City Clinical Hospital Sixty-seven
Email: 67gkb@mail.ru
ORCID iD: 0000-0002-9783-1796
MD, PhD, Professor
Russian Federation, 2/44, Salyama Adilya str., Moscow, 123423Liudmila S. Radetskaya
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: udaeva@gmail.com
ORCID iD: 0000-0003-3410-6885
SPIN-code: 4554-7324
MD, Associated Professor
Russian Federation, 8-2, Trubetskaya street, Moscow, 119992Alexander D. Makatsariya
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Author for correspondence.
Email: gemostasis@mail.ru
ORCID iD: 0000-0001-7415-4633
SPIN-code: 7538-2966
https://internist.ru/lectors/detail/makatsariya-/
MD, PhD, Academician of the RAS
Russian Federation, 8-2, Trubetskaya street, Moscow, 119992Ismail Elalamy
I.M. Sechenov Moscow State Medical University (Sechenov University); Medicine Sorbonne University, University Hospital Tenon
Email: ismail.elalamy@aphp.fr
ORCID iD: 0000-0002-9576-1368
Scopus Author ID: 7003652413
MD, PhD, Professor
Russian Federation, Trubetskaya str. 8-2, 119991; rue de la Chine 75970 Paris Cédex 20, FranceJean-Christophe Gris
I.M. Sechenov First Moscow State Medical University (Sechenov University); University Montpellier, France
Email: jean.christophe.gris@chu-nimes.fr
ORCID iD: 0000-0002-9899-9910
Scopus Author ID: 7005114260
MD, PhD, Professor
Russian Federation, Trubetskaya str. 8-2, 119991, Moscow; Place du Pr. Robert Debré 30039 Nîmes cédex 09Elvira Grandone
The First I.M. Sechenov Moscow State Medical University, (Sechenov University);Thrombosis and Haemostasis Research Unit, Fondazione I.R.C.C.S. "Casa Sollievo della Sofferenza"
Email: grandoneelvira@gmail.com
ORCID iD: 0000-0002-8980-9783
Scopus Author ID: 7006391091
MD, PhD, Professor, Department of thrombosis and hemostasis
Italy, Trubetskaya str. 8-2, 119991, Moscow; 71043, Viale Padre Pio, San Giovanni Rotondo, Foggia, ItalyReferences
- Burzynski LC, Humphry M, Pyrillou K, et al. The coagulation and immune systems are directly linked through the activation of interleukin-1α by thrombin. Immunity. 2019;50:1033–1042. doi: https://doi.org/10.1016/j.immuni.2019.03.003
- Bonaventura A, Montecucco F, Dallegri F, et al. Novel findings in neutrophil biology and their impact on cardiovascular disease. Cardiovasc Res. 2019;115:1266–1285. doi: https://doi.org/10.1093/cvr/cvz084
- Bonaventura A, Vecchié A, Abbate A, Montecucco F. Neutrophil extracellular traps and cardiovascular diseases: an update. Cells. 2020;9:231. doi: https://doi.org/10.3390/cells9010231
- Mitsios A, Arampatzioglou A, Arelaki S, et al. NETopathies? Unraveling the dark side of old diseases through neutrophils. Front Immunol. 2017;7:678. doi: https://doi.org/10.3389/fimmu.2016.00678
- Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23:279. doi: https://doi.org/10.1038/nm.4294
- Jiménez-Alcázar M, Rangaswamy C, Panda R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science. 2017;358:1202–1206. doi: https://doi.org/10.1126/science.aam8897
- Brinkmann V. Neutrophil extracellular traps in the second decade. J Innate Immun. 2018;10(5-6):414–421. doi: https://doi.org/10.1159/000489829
- Chen KW, Monteleone M, Boucher D, et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci Immunol. 2018;3(26):eaar6676. doi: https://doi.org/10.1126/sciimmunol.aar6676
- Chrysanthopoulou A, Kambas K, Stakos D, et al. Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation. J Pathol. 2017;243(1):111–122. doi: https://doi.org/10.1002/path.4935
- von Köckritz-Blickwede M, Goldmann O, Thulin P, et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood. 2008;111:3070–3080. doi: https://doi.org/10.1182/blood-2007-07-104018
- Pertiwi KR, de Boer OJ, Mackaaij C, et al. Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time‐dependent manner during atherothrombosis. J Pathol. 2019;247(4):505–512. doi: https://doi.org/10.1002/path.5212
- Marx C, Novotny J, Salbeck D, Zellner KR, Nicolai L, Pekayvaz K, et al. Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps. Blood. 2019;134:1859–1872. doi: https://doi.org/10.1182/blood.2019000518
- Grilz E, Mauracher LM, Posch F, et al. Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer. Br J Haematol. 2019;186:311–320. doi: https://doi.org/10.1111/bjh.15906
- Sollberger G, Tilley DO, Zychlinsky A. Neutrophil extracellular traps: the biology of chromatin externalization. Dev Cell. 2018;44:542–553. doi: https://doi.org/10.1016/j.devcel.2018.01.019
- Noubouossie DF, Whelihan MF, Yu Y-B, et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood. 2017;129:1021–1029. doi: https://doi.org/10.1182/blood-2016-06-722298
- Ivanov I, Shakhawat R, Sun M-F, et al. Nucleic acids as cofactors for factor XI and prekallikrein activation: Different roles for high-molecular-weight kininogen. Thromb Haemost. 2017;117(4):671–681. doi: https://doi.org/10.1160/TH16-09-0691
- Kordbacheh F, O’Meara CH, Coupland LA, et al. Extracellular histones induce erythrocyte fragility and anemia. Blood. 2017;130:2884–2888. doi: https://doi.org/10.1182/blood-2017-06-790519
- Okeke EB, Louttit C, Fry C, et al. Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock. Biomaterials. 2020;238:119836. doi: https://doi.org/10.1016/j.biomaterials.2020.119836
- Silvestre-Roig C, Braster Q, Wichapong K, et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature. 2019;569:236–240. doi: https://doi.org/10.1038/s41586-019-1167-6
- Wang Y, Luo L, Braun OÖ, et al. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci Rep. 2018;8:1–14. doi: https://doi.org/10.1038/s41598-018-22156-5
- Josefs T, Barrett TJ, Brown EJ, et al. Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice. JCI Insight. 2020;5. doi: https://doi.org/10.1172/jci.insight.134796
- Ashar HK, Mueller NC, Rudd JM, et al. The Role of Extracellular Histones in Influenza Virus Pathogenesis. Am J Pathol. 2018;188:135–148. doi: https://doi.org/10.1016/j.ajpath.2017.09.014
- Ducroux C, Di Meglio L, Loyau S, et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke. 2018;49:754–757. doi: https://doi.org/10.1161/STROKEAHA.117.019896
- Vallés J, Lago A, Santos MT, et al. Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance. Thromb Haemost. 2017;117:1919–1929. doi: https://doi.org/10.1160/TH17-02-0130
- Wolach O, Sellar RS, Martinod K, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Science Translational Medicine. 2018;10:eaan8292. doi: https://doi.org/10.1126/scitranslmed.aan8292
- Schedel F, Mayer‐Hain S, Pappelbaum KI, et al. Evidence and impact of neutrophil extracellular traps in malignant melanoma. Pigment Cell Melanoma Res. 2020;33(1):63–73. doi: https://doi.org/10.1111/pcmr.12818
- Teijeira Á, Garasa S, Gato M, et al. Cxcr1 and cxcr2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity. 2020;52(5):856–871.e8. doi: https://doi.org/10.1016/j.immuni.2020.03.001
- Yang L-Y, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13:1–15. doi: https://doi.org/10.1186/s13045-019-0836-0
- White C, Noble SI, Watson M, et al. Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): a prospective longitudinal observational study. Lancet Haematol. 2019;6:e79–e88. doi: https://doi.org/10.1016/S2352--3026(18)30215-1
- Demers M, Krause DS, Schatzberg D, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Nat Acad Sci. 2012;109(32):13076–13081. doi: https://doi.org/10.1073/pnas.1200419109
- Yang S, Qi H, Kan K, et al. Neutrophil extracellular traps promote hypercoagulability in patients with sepsis. Shock. 2017;47(2):132–139. doi: https://doi.org/10.1097/SHK.0000000000000741
- Delabranche X, Stiel L, Severac F, et al. Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock. 2017;47(3):313–317. doi: https://doi.org/10.1097/SHK.0000000000000719
- Kapoor S, Opneja A, Nayak L. The role of neutrophils in thrombosis. Thromb Res. 2018;170:87–96. doi: https://doi.org/10.1016/j.thromres.2018.08.005
- Duvvuri B, Pachman LM, Morgan G, et al. Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis. Arthritis Rheumatol. 2020;72(2):348–358. doi: https://doi.org/10.1002/art.41078
- Goel RR, Kaplan MJ. Deadliest catch: neutrophil extracellular traps in autoimmunity. Curr Op Rheumatol. 2020;32:64–70. doi: https://doi.org/10.1097/BOR.0000000000000667
- Angelidou I, Chrysanthopoulou A, Mitsios A, et al. REDD1/autophagy pathway is associated with neutrophil-driven IL-1β inflammatory response in active ulcerative colitis. J Immunol. 2018;200:3950–3961. doi: https://doi.org/10.4049/jimmunol.1701643
- Frangou E, Chrysanthopoulou A, Mitsios A, et al. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann Rheum Dis. 2019;78:238–248. doi: https://doi.org/10.1136/annrheumdis-2018-213181
- Meng H, Yalavarthi S, Kanthi Y, et al. In vivo role of neutrophil extracellular traps in antiphospholipid antibody–mediated venous thrombosis. Arthritis Rheumatol. 2017;69(3):655–667. doi: https://doi.org/10.1002/art.39938
- Gollomp K, Kim M, Johnston I, et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3(18):e99445. doi: https://doi.org/10.1172/jci.insight.99445
- Perdomo J, Leung HH, Ahmadi Z, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10:1–14. doi: https://doi.org/10.1038/s41467-019-09160-7
- Maugeri N, Capobianco A, Rovere-Querini P, et al. Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis. Sci Transl Med. 2018;10:eaao3089. doi: https://doi.org/10.1126/scitranslmed.aao3089
- Qi H, Yang S, Zhang L. Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol. 2017;8:928. doi: https://doi.org/10.3389/fimmu.2017.00928
- Wiseman SJ, Ralston SH, Wardlaw JM. Cerebrovascular disease in rheumatic diseases: a systematic review and meta-analysis. Stroke. 2016;47:943–950. doi: https://doi.org/10.1161/STROKEAHA.115.012052
- Agca R, Heslinga S, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76(1):17–28. doi: http://dx.doi.org/10.1136/annrheumdis-2016-209775
- Ali RA, Gandhi AA, Meng H, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nature Commun. 2019;10:1–12. doi: https://doi.org/10.1038/s41467-019-09801-x
- Knight JS, Meng H, Coit P, et al. Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight. 2017;2(18):e93897. doi: https://doi.org/10.1172/jci.insight.93897
- Weeding E, Coit P, Yalavarthi S, et al. Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol. 2018;196:110–116. doi: https://doi.org/10.1016/j.clim.2018.11.011
- Sharma A, McCann K, Tripathi JK, et al. Tamoxifen restores extracellular trap formation in neutrophils from patients with chronic granulomatous disease in a reactive oxygen species–independent manner. J Allergy Clin Immunol. 2019;144(2):597–600.e593. doi: https://doi.org/10.1016/j.jaci.2019.04.014
- Papagoras C, Chrysanthopoulou A, Mitsios A, et al. Autophagy inhibition in adult-onset Still’s disease: still more space for hydroxychloroquine? Clin Exp Rheumatol. 2017;35 Suppl 108 (6):133–134.
- Belizna C, Pregnolato F, Abad S, et al. HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome. Autoimmunity Reviews. 2018;17:1153–1168. doi: https://doi.org/10.1016/j.autrev.2018.05.012
- Manfredi AA, Rovere-Querini P, D’Angelo A, Maugeri N. Low molecular weight heparins prevent the induction of autophagy of activated neutrophils and the formation of neutrophil extracellular traps. Pharmacol Res. 2017;123:146–156. doi: https://doi.org/10.1016/j.phrs.2016.08.008
- Van Avondt K, Maegdefessel L, Soehnlein O. Therapeutic targeting of neutrophil extracellular traps in atherogenic inflammation. Thromb Haemost. 2019;119(4):542–552. doi: https://doi.org/10.1055/s-0039-1678664
- Mastellos DC, Reis ES, Ricklin D, et al. Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery. Trends Immunol. 2017;38(6):383–394. doi: https://doi.org/10.1016/j.it.2017.03.003
- 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. doi: https://doi.org/10.1186/s12885-018-4584-2
- Skendros P, Chrysanthopoulou A, Rousset F, al. Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps. J Allergy Clin Immunol. 2017;140(5):1378–1387.e1313. doi: https://doi.org/10.1016/j.jaci.2017.02.021
- Mauracher LM, Posch F, Martinod K, et al. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost. 2018;16(3):508–518. doi: https://doi.org/10.1111/jth.13951.
Supplementary files
