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NETs in APS: Current Knowledge and Future Perspectives

  • Antiphospholipid Syndrome (S Zuily, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease that is primarily treated with anticoagulation. Better understanding the inflammatory aspects of APS could lead to safer, more effective, and more personalized therapeutic options. To this end, we sought to understand recent literature related to the role of neutrophils and, in particular, neutrophil extracellular traps (NETs) in APS.

Recent Findings

Expression of genes associated with type I interferons, endothelial adhesion, and pregnancy regulation are increased in APS neutrophils. APS neutrophils have a reduced threshold for NET release, which likely potentiates thrombotic events and perhaps especially large-vein thrombosis. Neutrophil-derived reactive oxygen species also appear to play a role in APS pathogenesis. There are new approaches for preventing and disrupting NETs that could potentially be leveraged to reduce the risk of APS-associated thrombosis.

Summary

Neutrophils and NETs contribute to APS pathophysiology. More precisely understanding their roles at a mechanistic level should help identify new therapeutic targets for inhibiting NET formation, enhancing NET dissolution, and altering neutrophil adhesion. Such approaches may ultimately lead to better clinical management of APS patients and thereby reduce the chronic burden of this disease.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.

    CAS  PubMed  Google Scholar 

  2. Linnemann B. Antiphospholipid syndrome - an update. Vasa. 2018;47(6):451–64.

    PubMed  Google Scholar 

  3. Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, et al. 14th international congress on antiphospholipid antibodies task force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13(9):917–30.

    PubMed  Google Scholar 

  4. Uthman I, Noureldine MHA, Ruiz-Irastorza G, Khamashta M. Management of antiphospholipid syndrome. Ann Rheum Dis. 2019;78(2):155–61.

    CAS  PubMed  Google Scholar 

  5. Duarte-García A, Pham MM, Crowson CS, Amin S, Moder KG, Pruthi RK, et al. The epidemiology of antiphospholipid syndrome: a population-based Study. Arthritis Rheumatol. 2019;71(9):1545–52.

    PubMed  PubMed Central  Google Scholar 

  6. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346(10):752–63.

    CAS  PubMed  Google Scholar 

  7. Pons-Estel GJ, Andreoli L, Scanzi F, Cervera R, Tincani A. The antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun. 2017;76:10–20.

    CAS  PubMed  Google Scholar 

  8. Branch DW, Dudley DJ, Mitchell MD, Creighton KA, Abbott TM, Hammond EH, et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol. 1990;163(1 Pt 1):210–6.

    CAS  PubMed  Google Scholar 

  9. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A. 1991;88(8):3069–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Pierangeli SS, Barker JH, Stikovac D, Ackerman D, Anderson G, Barquinero J, et al. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice. Thromb Haemost. 1994;71(5):670–4.

    CAS  PubMed  Google Scholar 

  11. Lie JT. Vasculopathy of the antiphospholipid syndromes revisited: thrombosis is the culprit and vasculitis the consort. Lupus. 1996;5(5):368–71.

    CAS  PubMed  Google Scholar 

  12. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7):1309–11.

    CAS  PubMed  Google Scholar 

  13. • Chaturvedi S, Brodsky RA, McCrae KR. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol. 2019;10:449. This recent review highlights the role of complement in APS.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tedesco F, Borghi MO, Gerosa M, Chighizola CB, Macor P, Lonati PA, et al. Pathogenic role of complement in antiphospholipid syndrome and therapeutic implications. Front Immunol. 2018;9:1388.

    PubMed  PubMed Central  Google Scholar 

  15. de Groot PG, Urbanus RT. Antiphospholipid syndrome--not a noninflammatory disease. Semin Thromb Hemost. 2015;41(6):607–14.

    PubMed  Google Scholar 

  16. Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when beta 2-glycoprotein I is bound to a suitable surface. Thromb Haemost. 1995;73(1):29–34.

    CAS  PubMed  Google Scholar 

  17. Manfredi AA, Rovere P, Galati G, Heltai S, Bozzolo E, Soldini L, et al. Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum. 1998;41(2):205–14.

    CAS  PubMed  Google Scholar 

  18. Manfredi AA, Rovere P, Heltai S, Galati G, Nebbia G, Tincani A, et al. Apoptotic cell clearance in systemic lupus erythematosus. II. Role of beta2-glycoprotein I. Arthritis Rheum. 1998;41(2):215–23.

    CAS  PubMed  Google Scholar 

  19. Rovere P, Manfredi AA, Vallinoto C, Zimmermann VS, Fascio U, Balestrieri G, et al. Dendritic cells preferentially internalize apoptotic cells opsonized by anti-beta2-glycoprotein I antibodies. J Autoimmun. 1998;11(5):403–11.

    CAS  PubMed  Google Scholar 

  20. Rovere P, Sabbadini MG, Vallinoto C, Fascio U, Recigno M, Crosti M, et al. Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: role of opsonizing anti-beta2-glycoprotein I antibodies. Arthritis Rheum. 1999;42(7):1412–20.

    CAS  PubMed  Google Scholar 

  21. Sacharidou A, Chambliss KL, Ulrich V, Salmon JE, Shen YM, Herz J, et al. Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. Blood. 2018;131(19):2097–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mineo C, Lanier L, Jung E, Sengupta S, Ulrich V, Sacharidou A, et al. Identification of a monoclonal antibody that attenuates antiphospholipid syndrome-related pregnancy complications and thrombosis. PLoS One. 2016;11(7):e0158757.

    PubMed  PubMed Central  Google Scholar 

  23. Ulrich V, Gelber SE, Vukelic M, Sacharidou A, Herz J, Urbanus RT, et al. ApoE receptor 2 mediation of trophoblast dysfunction and pregnancy complications induced by antiphospholipid antibodies in mice. Arthritis Rheumatol. 2016;68(3):730–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Urbanus RT, Pennings MT, Derksen RH, de Groot PG. Platelet activation by dimeric beta2-glycoprotein I requires signaling via both glycoprotein Ibalpha and apolipoprotein E receptor 2′. J Thromb Haemost. 2008;6(8):1405–12.

    CAS  PubMed  Google Scholar 

  25. Ramesh S, Morrell CN, Tarango C, Thomas GD, Yuhanna IS, Girardi G, et al. Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2. J Clin Invest. 2011;121(1):120–31.

    CAS  PubMed  Google Scholar 

  26. Romay-Penabad Z, Aguilar-Valenzuela R, Urbanus RT, Derksen RH, Pennings MT, Papalardo E, et al. Apolipoprotein E receptor 2 is involved in the thrombotic complications in a murine model of the antiphospholipid syndrome. Blood. 2011;117(4):1408–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Allen KL, Hamik A, Jain MK, McCrae KR. Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors. Blood. 2011;117(23):6383–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B, Reber G, Kruithof EK. NFkappaB is an essential intermediate in the activation of endothelial cells by anti-beta(2)-glycoprotein 1 antibodies. Thromb Haemost. 2002;88(5):851–7.

    PubMed  Google Scholar 

  29. Vega-Ostertag M, Casper K, Swerlick R, Ferrara D, Harris EN, Pierangeli SS. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum. 2005;52(5):1545–54.

    CAS  PubMed  Google Scholar 

  30. Pierangeli SS, Espinola RG, Liu X, Harris EN. Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Circ Res. 2001;88(2):245–50.

    CAS  PubMed  Google Scholar 

  31. Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR, Salmon JE, et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest. 1995;96(5):2211–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Del Papa N, Guidali L, Sala A, Buccellati C, Khamashta MA, Ichikawa K, et al. Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-beta 2-glycoprotein I antibodies react in vitro with endothelial cells through adherent beta 2-glycoprotein I and induce endothelial activation. Arthritis Rheum. 1997;40(3):551–61.

    PubMed  Google Scholar 

  33. Espinola RG, Liu X, Colden-Stanfield M, Hall J, Harris EN, Pierangeli SS. E-Selectin mediates pathogenic effects of antiphospholipid antibodies. J Thromb Haemost. 2003;1(4):843–8.

    CAS  PubMed  Google Scholar 

  34. Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N, et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost. 2004;91(4):667–73.

    CAS  PubMed  Google Scholar 

  35. Chaturvedi S, Cockrell E, Espinola R, Hsi L, Fulton S, Khan M, et al. Circulating microparticles in patients with antiphospholipid antibodies: characterization and associations. Thromb Res. 2015;135(1):102–8.

    CAS  PubMed  Google Scholar 

  36. Ng LG, Ostuni R, Hidalgo A. Heterogeneity of neutrophils. Nat Rev Immunol. 2019;19(4):255–65.

    CAS  PubMed  Google Scholar 

  37. Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annu Rev Pathol. 2014;9:181–218.

    CAS  PubMed  Google Scholar 

  38. Grayson PC, Schauer C, Herrmann M, Kaplan MJ. Review: neutrophils as invigorated targets in rheumatic diseases. Arthritis Rheumatol. 2016;68(9):2071–82.

    PubMed  PubMed Central  Google Scholar 

  39. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5.

    CAS  PubMed  Google Scholar 

  40. Steinberg BE, Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE. 2007;2007(379):pe11.

    PubMed  Google Scholar 

  41. Brinkmann V. Neutrophil extracellular traps in the second decade. J Innate Immun. 2018;10(5–6):414–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. • Boeltz S, Amini P, Anders HJ, Andrade F, Bilyy R, Chatfield S, et al. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell Death Differ. 2019;26(3):395–408. This review summarizes the current state of NET research.

    PubMed  PubMed Central  Google Scholar 

  43. Euler M, Hoffmann MH. The double-edged role of neutrophil extracellular traps in inflammation. Biochem Soc Trans. 2019;47(6):1921–30.

    CAS  PubMed  Google Scholar 

  44. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34–45.

    CAS  PubMed  Google Scholar 

  45. von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819–35.

    Google Scholar 

  46. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463–9.

    CAS  PubMed  Google Scholar 

  47. McDonald B, 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(10):1357–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16(8):887–96.

    CAS  PubMed  Google Scholar 

  49. Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109(32):13076–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10(1):136–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol. 2014;34(9):1977–84.

    CAS  PubMed  Google Scholar 

  52. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kambas K, Mitroulis I, Apostolidou E, Girod A, Chrysanthopoulou A, Pneumatikos I, et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLoS One. 2012;7(9):e45427.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in thrombosis-the journey of TF through NETs. Front Immunol. 2012;3:385.

    PubMed  PubMed Central  Google Scholar 

  55. Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One. 2012;7(2):e32366.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Oehmcke S, Mörgelin M, Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun. 2009;1(3):225–30.

    PubMed  PubMed Central  Google Scholar 

  57. Thomas GM, Brill A, Mezouar S, Crescence L, Gallant M, Dubois C, et al. Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice. J Thromb Haemost. 2015;13(7):1310–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Stakos DA, Kambas K, Konstantinidis T, Mitroulis I, Apostolidou E, Arelaki S, et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J. 2015;36(22):1405–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62(2):600–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123(24):3818–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, Monestier M, et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122(7):2661–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yago T, Liu Z, Ahamed J, McEver RP. Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice. Blood. 2018;132(13):1426–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Etulain J, Martinod K, Wong SL, Cifuni SM, Schattner M, Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126(2):242–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A. 2013;110(21):8674–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. de Boer OJ, Li X, Teeling P, Mackaay C, Ploegmakers HJ, van der Loos CM, et al. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb Haemost. 2013;109(2):290–7.

    PubMed  Google Scholar 

  66. Borissoff JI, Joosen IA, Versteylen MO, Brill A, Fuchs TA, Savchenko AS, et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol. 2013;33(8):2032–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Maugeri N, Campana L, Gavina M, Covino C, De Metrio M, Panciroli C, et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost. 2014;12(12):2074–88.

    CAS  PubMed  Google Scholar 

  68. Mangold A, Alias S, Scherz T, Hofbauer T, Jakowitsch J, Panzenböck A, et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. 2015;116(7):1182–92.

    CAS  PubMed  Google Scholar 

  69. Vallés J, Lago A, Santos MT, Latorre AM, Tembl JI, Salom JB, et al. Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance. Thromb Haemost. 2017;117(10):1919–29.

    PubMed  Google Scholar 

  70. Laridan E, Denorme F, Desender L, François O, Andersson T, Deckmyn H, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol. 2017;82(2):223–32.

    CAS  PubMed  Google Scholar 

  71. Ducroux C, Di Meglio L, Loyau S, Delbosc S, Boisseau W, Deschildre C, et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke. 2018;49(3):754–7.

    PubMed  Google Scholar 

  72. Farkas Á, Farkas VJ, Gubucz I, Szabó L, Bálint K, Tenekedjiev K, et al. Neutrophil extracellular traps in thrombi retrieved during interventional treatment of ischemic arterial diseases. Thromb Res. 2019;175:46–52.

    CAS  PubMed  Google Scholar 

  73. van Montfoort ML, Stephan F, Lauw MN, Hutten BA, Van Mierlo GJ, Solati S, et al. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2013;33(1):147–51.

    PubMed  Google Scholar 

  74. Diaz JA, Fuchs TA, Jackson TO, Kremer Hovinga JA, Lämmle B, Henke PK, et al. Plasma DNA is elevated in patients with deep vein thrombosis. J Vasc Surg Venous Lymphat Disord. 2013;1(4).

  75. Savchenko AS, Martinod K, Seidman MA, Wong SL, Borissoff JI, Piazza G, et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost. 2014;12(6):860–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood. 2012;120(6):1157–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Mikes B, Sinkovits G, Farkas P, Csuka D, Schlammadinger A, Rázsó K, et al. Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura. Thromb Res. 2014;133(4):616–21.

    CAS  PubMed  Google Scholar 

  78. Jiménez-Alcázar M, Napirei M, Panda R, Köhler EC, Kremer Hovinga JA, Mannherz HG, et al. Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost. 2015;13(5):732–42.

    PubMed  Google Scholar 

  79. Arvieux J, Jacob MC, Roussel B, Bensa JC, Colomb MG. Neutrophil activation by anti-beta 2 glycoprotein I monoclonal antibodies via Fc gamma receptor II. J Leukoc Biol. 1995;57(3):387–94.

    CAS  PubMed  Google Scholar 

  80. Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Redecha P, Tilley R, Tencati M, Salmon JE, Kirchhofer D, Mackman N, et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood. 2007;110(7):2423–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Redecha P, Franzke CW, Ruf W, Mackman N, Girardi G. Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J Clin Invest. 2008;118(10):3453–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. IMPACT Study: IMProve pregnancy in APS With certolizumab therapy. https://ClinicalTrials.gov/show/NCT03152058.

  84. Marder W, Knight JS, Kaplan MJ, Somers EC, Zhang X, O'Dell AA, et al. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci Med. 2016;3(1):e000134.

    PubMed  PubMed Central  Google Scholar 

  85. Erpenbeck L, Chowdhury CS, Zsengellér ZK, Gallant M, Burke SD, Cifuni S, et al. PAD4 deficiency decreases inflammation and susceptibility to pregnancy loss in a mouse model. Biol Reprod. 2016;95(6):132.

    PubMed  PubMed Central  Google Scholar 

  86. Mizugishi K, Yamashita K. Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase-deficient mice on 129Sv/C57BL/6 background. FASEB J. 2017;31(12):5577–91.

    CAS  PubMed  Google Scholar 

  87. Gladigau G, Haselmayer P, Scharrer I, Munder M, Prinz N, Lackner K, et al. A role for toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome. PLoS One. 2012;7(7):e42176.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006;177(7):4794–802.

    CAS  PubMed  Google Scholar 

  89. Leffler J, Stojanovich L, Shoenfeld Y, Bogdanovic G, Hesselstrand R, Blom AM. Degradation of neutrophil extracellular traps is decreased in patients with antiphospholipid syndrome. Clin Exp Rheumatol. 2014;32(1):66–70.

    PubMed  Google Scholar 

  90. Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris AE, Nunez-Alvarez C, et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015;67(11):2990–3003.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. • Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfline MA, Luke CE, et al. In vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheumatol. 2017;69(3):655–67. This study demonstrated that administration of APS patient IgG to mice led to larger thrombi, and that these thrombi were enriched for NETs.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. • Sule G, Kelley WJ, Gockman K, Yalavarthi S, Vreede AP, Banka AL, et al. Increased adhesive potential of antiphospholipid syndrome neutrophils mediated by β2 integrin Mac-1. Arthritis Rheumatol. 2020;72(1):114–24. This study demonstrated the important role of Mac-1 in APS neutrophil adhesion and NETosis.

    CAS  PubMed  Google Scholar 

  93. • Knight JS, Meng H, Coit P, Yalavarthi S, Sule G, Gandhi AA, et al. Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight. 2017;2(18). This study performed transcriptomic analysis of APS neutrophils showing upregulation of interferon signaliing. The paper also demonstrated that PSGL-1 inhibition protected against NETosis and murine venous thrombosis.

  94. • Ali RA, Gandhi AA, Meng H, Yalavarthi S, Vreede AP, Estes SK, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat Commun. 2019;10(1):1916. This study demonstrated that activation of cell surface adenosine receptors, specifically the A2A receptor, could be used to reduce APS-associated NETosis and venous thrombosis.

    PubMed  PubMed Central  Google Scholar 

  95. • Zha C, Zhang W, Gao F, Xu J, Jia R, Cai J, et al. Anti-β2GPI/β2GPI induces neutrophil extracellular traps formation to promote thrombogenesis via the TLR4/MyD88/MAPKs axis activation. Neuropharmacology. 2018;138:140–50. This study demonstrated that aβ2GPI/β2GPI complexes generated more NETs than either species alone in a model of arterial APS.

    CAS  PubMed  Google Scholar 

  96. Pierangeli SS, Vega-Ostertag ME, Raschi E, Liu X, Romay-Penabad Z, De Micheli V, et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis. 2007;66(10):1327–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Knight JS, Zhao W, Luo W, Subramanian V, O'Dell AA, Yalavarthi S, et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123(7):2981–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Jiménez-Alcázar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science. 2017;358(6367):1202–6.

    PubMed  Google Scholar 

  99. 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(3):189–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wolach O, Sellar RS, Martinod K, Cherpokova D, McConkey M, Chappell RJ, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med. 2018;10(436).

  101. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. 2017;69(1):148–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lapponi MJ, Carestia A, Landoni VI, Rivadeneyra L, Etulain J, Negrotto S, et al. Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J Pharmacol Exp Ther. 2013;345(3):430–7.

    CAS  PubMed  Google Scholar 

  103. 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;123:146–56.

    CAS  PubMed  Google Scholar 

  104. Müller-Calleja N, Manukyan D, Canisius A, Strand D, Lackner KJ. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis. 2017;76(5):891–7.

    PubMed  Google Scholar 

  105. Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, et al. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol. 2014;66(9):2532–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Handono K, Sidarta YO, Pradana BA, Nugroho RA, Hartono IA, Kalim H, et al. Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus. Acta Med Indones. 2014;46(3):189–98.

    PubMed  Google Scholar 

  107. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol 2014;192(12):5459–5468.

  108. Xourgia E, Tektonidou MG. Type I interferon gene expression in antiphospholipid syndrome: pathogenetic, clinical and therapeutic implications. J Autoimmun. 2019;104:102311.

    CAS  PubMed  Google Scholar 

  109. Grenn RC, Yalavarthi S, Gandhi AA, Kazzaz NM, Núñez-Álvarez C, Hernández-Ramírez D, et al. Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome. Ann Rheum Dis. 2017;76(2):450–7.

    CAS  PubMed  Google Scholar 

  110. van den Hoogen LL, Fritsch-Stork RD, Versnel MA, Derksen RH, van Roon JA, Radstake TR. Monocyte type I interferon signature in antiphospholipid syndrome is related to proinflammatory monocyte subsets, hydroxychloroquine and statin use. Ann Rheum Dis. 2016;75(12):e81.

    PubMed  Google Scholar 

  111. Palli E, Kravvariti E, Tektonidou MG. Type I interferon signature in primary antiphospholipid syndrome: clinical and laboratory associations. Front Immunol. 2019;10:487.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ugolini-Lopes MR, Torrezan GT, Gândara APR, Olivieri EHR, Nascimento IS, Okazaki E, et al. Enhanced type I interferon gene signature in primary antiphospholipid syndrome: association with earlier disease onset and preeclampsia. Autoimmun Rev. 2019;18(4):393–8.

    CAS  PubMed  Google Scholar 

  113. Leroy V, Arvieux J, Jacob MC, Maynard-Muet M, Baud M, Zarski JP. Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol. 1998;101(3):468–74.

    CAS  PubMed  Google Scholar 

  114. Balderramo DC, García O, Colmenero J, Espinosa G, Forns X, Ginès P. Antiphospholipid syndrome during pegylated interferon alpha-2a therapy for chronic hepatitis C. Dig Liver Dis. 2009;41(7):e4–7.

    CAS  PubMed  Google Scholar 

  115. • Weeding E, Coit P, Yalavarthi S, Kaplan MJ, Knight JS, Sawalha AH. Genome-wide DNA Methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol. 2018;196:110–6. This study performed genome-wide DNA methylation analysis of APS neutrophils and revealed hypomethylation of genes involved in mammalian pregnancy.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. • Ripoll VM, Pregnolato F, Mazza S, Bodio C, Grossi C, McDonnell T, et al. Gene expression profiling identifies distinct molecular signatures in thrombotic and obstetric antiphospholipid syndrome. J Autoimmun. 2018;93:114–23. The study demonstrated differentially upregulated genes in monocytes cultured with IgG from patients with thrombotic versus obstetric APS.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Hacbarth E, Kajdacsy-Balla A. Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 1986;29(11):1334–42.

    CAS  PubMed  Google Scholar 

  118. 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(6):3284–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Carmona-Rivera C, Kaplan MJ. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol. 2013;35(4):455–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187(1):538–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3(73):73ra19.

    PubMed  PubMed Central  Google Scholar 

  123. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3(73):73ra20.

    PubMed  PubMed Central  Google Scholar 

  124. Zhang S, Lu X, Shu X, Tian X, Yang H, Yang W, et al. Elevated plasma cfDNA may be associated with active lupus nephritis and partially attributed to abnormal regulation of neutrophil extracellular traps (NETs) in patients with systemic lupus erythematosus. Intern Med. 2014;53(24):2763–71.

    PubMed  Google Scholar 

  125. van den Hoogen LL, Fritsch-Stork RD, van Roon JA, Radstake TR. Low-density granulocytes are increased in antiphospholipid syndrome and are associated with anti-β2 -glycoprotein I antibodies: comment on the article by Yalavarthi et al. Arthritis Rheumatol. 2016;68(5):1320–1.

    PubMed  Google Scholar 

  126. van den Hoogen LL, van der Linden M, Meyaard L, Fritsch-Stork RDE, van Roon JA, Radstake TR. Neutrophil extracellular traps and low-density granulocytes are associated with the interferon signature in systemic lupus erythematosus, but not in antiphospholipid syndrome. Ann Rheum Dis. 2019.

  127. van der Linden M, van den Hoogen LL, Westerlaken GHA, Fritsch-Stork RDE, van Roon JAG, Radstake TRDJ, et al. Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome. Rheumatology (Oxford). 2018;57(7):1228–34.

    Google Scholar 

  128. Hoffmann MH, Griffiths HR. The dual role of reactive oxygen species in autoimmune and inflammatory diseases: evidence from preclinical models. Free Radic Biol Med. 2018;125:62–71.

    CAS  PubMed  Google Scholar 

  129. Olsson LM, Lindqvist AK, Källberg H, Padyukov L, Burkhardt H, Alfredsson L, et al. A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity. Arthritis Res Ther. 2007;9(5):R98.

    PubMed  PubMed Central  Google Scholar 

  130. Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet. 2017;49(3):433–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Jacob CO, Eisenstein M, Dinauer MC, Ming W, Liu Q, John S, et al. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc Natl Acad Sci U S A. 2012;109(2):E59–67.

    CAS  PubMed  Google Scholar 

  132. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, Zychlinsky A, et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7(2):75–7.

    CAS  PubMed  Google Scholar 

  134. Potera RM, Jensen MJ, Hilkin BM, South GK, Hook JS, Gross EA, et al. Neutrophil azurophilic granule exocytosis is primed by TNF-α and partially regulated by NADPH oxidase. Innate Immun. 2016;22(8):635–46.

    PubMed  PubMed Central  Google Scholar 

  135. Ames PR, Nourooz-Zadeh J, Tommasino C, Alves J, Brancaccio V, Anggard EE. Oxidative stress in primary antiphospholipid syndrome. Thromb Haemost. 1998;79(2):447–9.

    CAS  PubMed  Google Scholar 

  136. Delgado Alves J, Ames PR, Donohue S, Stanyer L, Nourooz-Zadeh J, Ravirajan C, et al. Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arthritis Rheum. 2002;46(10):2686–94.

    CAS  PubMed  Google Scholar 

  137. Charakida M, Besler C, Batuca JR, Sangle S, Marques S, Sousa M, et al. Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. JAMA. 2009;302(11):1210–7.

    CAS  PubMed  Google Scholar 

  138. Alves JD, Grima B. Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep. 2003;5(5):383–90.

    PubMed  Google Scholar 

  139. Morrow JD, Roberts LJ. The isoprostanes. Current knowledge and directions for future research. Biochem Pharmacol. 1996;51(1):1–9.

    CAS  PubMed  Google Scholar 

  140. Iuliano L, Praticò D, Ferro D, Pittoni V, Valesini G, Lawson J, et al. Enhanced lipid peroxidation in patients positive for antiphospholipid antibodies. Blood. 1997;90(10):3931–5.

    CAS  PubMed  Google Scholar 

  141. Sciascia S, Roccatello D, Bertero MT, Di Simone D, Cosseddu D, Vaccarino A, et al. 8-isoprostane, prostaglandin E2, C-reactive protein and serum amyloid A as markers of inflammation and oxidative stress in antiphospholipid syndrome: a pilot study. Inflamm Res. 2012;61(8):809–16.

    CAS  PubMed  Google Scholar 

  142. Perez-Sanchez C, Ruiz-Limon P, Aguirre MA, Bertolaccini ML, Khamashta MA, Rodriguez-Ariza A, et al. Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment. Blood. 2012;119(24):5859–70.

    CAS  PubMed  Google Scholar 

  143. • Pérez-Sánchez C, Aguirre M, Ruiz-Limón P, Ábalos-Aguilera MC, Jiménez-Gómez Y, Arias-de la Rosa I, et al. Ubiquinol effects on antiphospholipid syndrome Prothrombotic profile: a randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol. 2017;37(10):1923–32. This study demonstrated that APS patients administered ubiquinol had decreased oxidative stress and NETosis.

    PubMed  Google Scholar 

  144. • Linge P, Arve S, Olsson LM, Leonard D, Sjöwall C, Frodlund M, et al. NCF1–339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus. Ann Rheum Dis. 2020;79(2):254–61. This study demonstrated that lupus patients with a NOX2 polymorphism had increased risk for APS, higher interferon activity, lower ROS production, and a lower amount of NOX2-mediated NETosis.

    CAS  PubMed  Google Scholar 

  145. Brehm SP, Hoch SO, Hoch JA. DNA-binding proteins in human serum. Biochem Biophys Res Commun. 1975;63(1):24–31.

    CAS  PubMed  Google Scholar 

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Funding

AT was partially supported by the VA Healthcare System. JSK was supported by grants from the Lupus Research Alliance and Burroughs Wellcome Fund.

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  1. Division of Pediatric Rheumatology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Ajay Tambralli

  2. Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5678, USA

    Ajay Tambralli, Kelsey Gockman & Jason S. Knight

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Tambralli, A., Gockman, K. & Knight, J.S. NETs in APS: Current Knowledge and Future Perspectives. Curr Rheumatol Rep 22, 67 (2020). https://doi.org/10.1007/s11926-020-00936-1

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