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NETosis in Rheumatic Diseases

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Neutrophils are the most numerous and the first responder cells of the innate immune system. Evidence suggests that neutrophils may play an essential role in the pathogenesis of multiple systemic diseases. A novel mechanism of neutrophil extracellular traps (NETs) leading to breaking of self-tolerance and generation of autoimmune responses in predisposed individuals has been described in various autoimmune conditions. The purpose of the review is to identify these important mechanisms of NETs leading to autoimmunity in various rheumatic diseases.

Recent Findings

NETs contain histone and chromatin, which contain important autoantigens. Many autoimmune conditions are associated with increased NET-generating capacity, unique low-density granulocyte population, and impaired NET degradation leading to persistent inflammation and tissue damage. NETs can also activate other immune cells, and their components may amplify the inflammatory response by activation of complement pathways and inflammasomes. NETs can also contribute to autoantibody formation in disorders such as rheumatoid arthritis, ANCA-associated vasculitis, and systemic lupus erythematosus by providing a constant source of autoantigens. NETs can also serve as biomarkers providing insights into disease diagnosis and therapeutics.

Summary

NETs seem to play a primary role in inflammatory disease pathogenesis. Identification of different NET pathogenic pathways in various rheumatic conditions could provide new insights into disease pathogenesis and therapeutic targets could be developed towards the future treatment of inflammatory autoimmune diseases.

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References

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

  1. Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol. 2014;5:508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood. 1998;92(9):3007–17.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 2009;184(2):205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mollerherm H, von Kockritz-Blickwede M, Branitzki-Heinemann K. Antimicrobial activity of mast cells: role and relevance of extracellular DNA traps. Front Immunol. 2016;7:265.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Schorn C, Janko C, Latzko M, Chaurio R, Schett G, Herrmann M. Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells. Front Immunol. 2012;3:277.

    PubMed  PubMed Central  Google Scholar 

  7. •• Apel F, Zychlinsky A, Kenny EF. The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol. 2018;14(8):467–75 An important review article describing the role of neutrophil extracellular traps in rheumatic disease.

    Article  CAS  PubMed  Google Scholar 

  8. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006;16(4):396–400.

    Article  CAS  PubMed  Google Scholar 

  9. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006;8(4):668–76.

    Article  CAS  PubMed  Google Scholar 

  10. Diaz-Godinez C, Carrero JC. The state of art of neutrophil extracellular traps in protozoan and helminthic infections. Biosci Rep. 2019;39(1).

  11. Granger V, Peyneau M, Chollet-Martin S, de Chaisemartin L. Neutrophil extracellular traps in autoimmunity and allergy: immune complexes at work. Front Immunol. 2019;10:2824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gupta S, Kaplan MJ. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol. 2016;12(7):402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Martinelli S, Urosevic M, Daryadel A, Oberholzer PA, Baumann C, Fey MF, et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem. 2004;279(42):44123–32.

    Article  CAS  PubMed  Google Scholar 

  15. Gonzalez-Aparicio M, Alfaro C. Influence of interleukin-8 and neutrophil extracellular trap (NET) formation in the tumor microenvironment: is there a pathogenic role? J Immunol Res. 2019;2019:6252138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Aleman OR, Mora N, Cortes-Vieyra R, Uribe-Querol E, Rosales C. Transforming growth factor-beta-activated kinase 1 is required for human FcgammaRIIIb-induced neutrophil extracellular trap formation. Front Immunol. 2016;7:277.

    Article  PubMed  PubMed Central  Google Scholar 

  17. • Soderberg D, Segelmark M. Neutrophil extracellular traps in ANCA-associated vasculitis. Front Immunol. 2016;7:256 An important article describing the role of NETs in the pathogenesis of AAV.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Majewski P, Majchrzak-Gorecka M, Grygier B, Skrzeczynska-Moncznik J, Osiecka O, Cichy J. Inhibitors of serine proteases in regulating the production and function of neutrophil extracellular traps. Front Immunol. 2016;7:261.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Papayannopoulos V, Staab D, Zychlinsky A. Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One. 2011;6(12):e28526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Munoz LE, Kaplan MJ, Radic M, Herrmann M. Editorial: NETosis 2: the excitement continues. Front Immunol. 2017;8:1318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. •• Fousert E, Toes R, Desai J. Neutrophil extracellular traps (NETs) take the central stage in driving autoimmune responses. Cells. 2020;9(4) An important review describing the role of NETs as a central regulator in inflammation and autoimmunity.

  22. • Gestermann N, Di Domizio J, Lande R, Demaria O, Frasca L, Feldmeyer L, et al. Netting neutrophils activate autoreactive B cells in lupus. J Immunol. 2018;200(10):3364–71 This paper highlighted an important association between neutrophil activation, NET formation and B cell activation.

    Article  CAS  PubMed  Google Scholar 

  23. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013;190(3):1217–26.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Farrera C, Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol. 2013;191(5):2647–56.

    Article  CAS  PubMed  Google Scholar 

  26. Lazzaretto B, Fadeel B. Intra- and extracellular degradation of neutrophil extracellular traps by macrophages and dendritic cells. J Immunol. 2019;203(8):2276–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Donis-Maturano L, Sanchez-Torres LE, Cerbulo-Vazquez A, Chacon-Salinas R, Garcia-Romo GS, Orozco-Uribe MC, et al. Prolonged exposure to neutrophil extracellular traps can induce mitochondrial damage in macrophages and dendritic cells. Springerplus. 2015;4:161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hu Q, Shi H, Zeng T, Liu H, Su Y, Cheng X, et al. Increased neutrophil extracellular traps activate NLRP3 and inflammatory macrophages in adult-onset Still’s disease. Arthritis Res Ther. 2019;21(1):9.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sil P, Wicklum H, Surell C, Rada B. Macrophage-derived IL-1beta enhances monosodium urate crystal-triggered NET formation. Inflamm Res. 2017;66(3):227–37.

    Article  CAS  PubMed  Google Scholar 

  30. Minns D, Smith KJ, Findlay EG. Orchestration of adaptive T cell responses by neutrophil granule contents. Mediat Inflamm. 2019;2019:8968943.

    Article  CAS  Google Scholar 

  31. • Tillack K, Breiden P, Martin R, Sospedra M. T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J Immunol. 2012;188(7):3150–9 This important study established an important link between innate and adaptive immunity by identifying NET-mediated T cell activation.

    Article  CAS  PubMed  Google Scholar 

  32. Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2(10).

  33. Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol. 2012;188(7):3522–31.

    Article  CAS  PubMed  Google Scholar 

  34. Wang H, Wang C, Zhao MH, Chen M. Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol. 2015;181(3):518–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ma YH, Ma TT, Wang C, Wang H, Chang DY, Chen M, et al. High-mobility group box 1 potentiates antineutrophil cytoplasmic antibody-inducing neutrophil extracellular traps formation. Arthritis Res Ther. 2016;18:2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Barrientos L, Bignon A, Gueguen C, de Chaisemartin L, Gorges R, Sandre C, et al. Neutrophil extracellular traps downregulate lipopolysaccharide-induced activation of monocyte-derived dendritic cells. J Immunol. 2014;193(11):5689–98.

    Article  CAS  PubMed  Google Scholar 

  38. Sangaletti S, Tripodo C, Chiodoni C, Guarnotta C, Cappetti B, Casalini P, et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood. 2012;120(15):3007–18.

    Article  CAS  PubMed  Google Scholar 

  39. Harris HE, Andersson U, Pisetsky DS. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol. 2012;8(4):195–202.

    Article  CAS  PubMed  Google Scholar 

  40. Rahman S, Sagar D, Hanna RN, Lightfoot YL, Mistry P, Smith CK, et al. Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus. Ann Rheum Dis. 2019;78(7):957–66.

    Article  CAS  PubMed  Google Scholar 

  41. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12):5459–68.

    Article  CAS  PubMed  Google Scholar 

  42. Liu CL, Tangsombatvisit S, Rosenberg JM, Mandelbaum G, Gillespie EC, Gozani OP, et al. Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies. Arthritis Res Ther. 2012;14(1):R25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A. 2010;107(21):9813–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Leffler J, Gullstrand B, Jonsen A, Nilsson JA, Martin M, Blom AM, et al. Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. Arthritis Res Ther. 2013;15(4):R84.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. • Carmona-Rivera C, Kaplan MJ. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol. 2013;35(4):455–63 An important review highlighting the role of low-density granulocyte population and their role in NET formation and in systemic autoimmune disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2015;74(7):1417–24.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Jariwala MP, Laxer RM. Primary vasculitis in childhood: GPA and MPA in childhood. Front Pediatr. 2018;6:226.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Grayson PC, Carmona-Rivera C, Xu L, Lim N, Gao Z, Asare AL, et al. Neutrophil-related gene expression and low-density granulocytes associated with disease activity and response to treatment in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 2015;67(7):1922–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoshida M, Sasaki M, Sugisaki K, Yamaguchi Y, Yamada M. Neutrophil extracellular trap components in fibrinoid necrosis of the kidney with myeloperoxidase-ANCA-associated vasculitis. Clin Kidney J. 2013;6(3):308–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nakazawa D, Shida H, Tomaru U, Yoshida M, Nishio S, Atsumi T, et al. Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis. J Am Soc Nephrol. 2014;25(5):990–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jimenez-Alcazar 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.

    Article  CAS  PubMed  Google Scholar 

  58. Kumar SV, Kulkarni OP, Mulay SR, Darisipudi MN, Romoli S, Thomasova D, et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol. 2015;26(10):2399–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kraaij T, Kamerling SWA, van Dam LS, Bakker JA, Bajema IM, Page T, et al. Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA. Kidney Int. 2018;94(1):139–49.

    Article  CAS  PubMed  Google Scholar 

  60. Futamata E, Masuda S, Nishibata Y, Tanaka S, Tomaru U, Ishizu A. Vanishing immunoglobulins: the formation of pauci-immune lesions in myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis. Nephron. 2018;138(4):328–30.

    Article  CAS  PubMed  Google Scholar 

  61. Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin MC, et al. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007;56(11):3541–53.

    Article  CAS  PubMed  Google Scholar 

  62. Cascao R, Rosario HS, Souto-Carneiro MM, Fonseca JE. Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmun Rev. 2010;9(8):531–5.

    Article  CAS  PubMed  Google Scholar 

  63. Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 1997;40(2):217–25.

    Article  CAS  PubMed  Google Scholar 

  64. Fossati G, Moots RJ, Bucknall RC, Edwards SW. Differential role of neutrophil Fcgamma receptor IIIB (CD16) in phagocytosis, bacterial killing, and responses to immune complexes. Arthritis Rheum. 2002;46(5):1351–61.

    Article  CAS  PubMed  Google Scholar 

  65. Van Steendam K, Tilleman K, De Ceuleneer M, De Keyser F, Elewaut D, Deforce D. Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins. Arthritis Res Ther. 2010;12(4):R132.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. • Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178):178ra40 This group described the role of NETosis in RA, identified the triggers, and described the deleterious inflammatory outcomes of NET formation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Sur Chowdhury C, Giaglis S, Walker UA, Buser A, Hahn S, Hasler P. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res Ther. 2014;16(3):R122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Corsiero E, Pratesi F, Prediletto E, Bombardieri M, Migliorini P. NETosis as source of autoantigens in rheumatoid arthritis. Front Immunol. 2016;7:485.

    PubMed  PubMed Central  Google Scholar 

  69. Bawadekar M, Shim D, Johnson CJ, Warner TF, Rebernick R, Damgaard D, et al. Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation. J Autoimmun. 2017;80:39–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chang HH, Dwivedi N, Nicholas AP, Ho IC. The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis. Arthritis Rheumatol. 2015;67(9):2323–34.

    Article  CAS  PubMed  Google Scholar 

  71. Tran CN, Davis MJ, Tesmer LA, Endres JL, Motyl CD, Smuda C, et al. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes. Arthritis Rheum. 2007;56(5):1497–506.

    Article  CAS  PubMed  Google Scholar 

  72. Kinloch AJ, Alzabin S, Brintnell W, Wilson E, Barra L, Wegner N, et al. Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian alpha-enolase and arthritis in DR4-IE-transgenic mice. Arthritis Rheum. 2011;63(12):3818–23.

    Article  CAS  PubMed  Google Scholar 

  73. Perricone C, Ceccarelli F, Saccucci M, Di Carlo G, Bogdanos DP, Lucchetti R, et al. Porphyromonas gingivalis and rheumatoid arthritis. Curr Opin Rheumatol. 2019;31(5):517–24.

    Article  CAS  PubMed  Google Scholar 

  74. Wright HL, Makki FA, Moots RJ, Edwards SW. Low-density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalling. J Leukoc Biol. 2017;101(2):599–611.

    Article  CAS  PubMed  Google Scholar 

  75. Perez-Sanchez C, Ruiz-Limon P, Aguirre MA, Jimenez-Gomez Y, Arias-de la Rosa I, Abalos-Aguilera MC, et al. Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in rheumatoid arthritis patients. J Autoimmun. 2017;82:31–40.

    Article  CAS  PubMed  Google Scholar 

  76. Punzi L, Scanu A, Ramonda R, Oliviero F. Gout as autoinflammatory disease: new mechanisms for more appropriated treatment targets. Autoimmun Rev. 2012;12(1):66–71.

    Article  CAS  PubMed  Google Scholar 

  77. Martinon F. Update on biology: uric acid and the activation of immune and inflammatory cells. Curr Rheumatol Rep. 2010;12(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  78. Mitroulis I, Kambas K, Ritis K. Neutrophils, IL-1beta, and gout: is there a link? Semin Immunopathol. 2013;35(4):501–12.

    Article  CAS  PubMed  Google Scholar 

  79. Popa-Nita O, Naccache PH. Crystal-induced neutrophil activation. Immunol Cell Biol. 2010;88(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  80. Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I, et al. Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLoS One. 2011;6(12):e29318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20(5):511–7.

    Article  CAS  PubMed  Google Scholar 

  82. Reber LL, Gaudenzio N, Starkl P, Galli SJ. Neutrophils are not required for resolution of acute gouty arthritis in mice. Nat Med. 2016;22(12):1382–4.

    Article  CAS  PubMed  Google Scholar 

  83. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7(6):330–9.

    Article  CAS  PubMed  Google Scholar 

  84. 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-beta2 -glycoprotein I antibodies: comment on the article by Yalavarthi et al. Arthritis Rheumatol. 2016;68(5):1320–1.

    PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 

  87. Bravo-Barrera J, Kourilovitch M, Galarza-Maldonado C. Neutrophil extracellular traps, antiphospholipid antibodies and treatment. Antibodies (Basel). 2017;6(1).

  88. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost. 2015;13(Suppl 1):S82–91.

    Article  CAS  PubMed  Google Scholar 

  90. Pinegin B, Vorobjeva N, Pinegin V. Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. Autoimmun Rev. 2015;14(7):633–40.

    Article  CAS  PubMed  Google Scholar 

  91. Renne T, Stavrou EX. Roles of factor XII in innate immunity. Front Immunol. 2019;10:2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shohat M, Halpern GJ. Familial Mediterranean fever--a review. Genet Med. 2011;13(6):487–98.

    Article  PubMed  Google Scholar 

  93. Apostolidou E, Skendros P, Kambas K, Mitroulis I, Konstantinidis T, Chrysanthopoulou A, et al. Neutrophil extracellular traps regulate IL-1beta-mediated inflammation in familial Mediterranean fever. Ann Rheum Dis. 2016;75(1):269–77.

    Article  CAS  PubMed  Google Scholar 

  94. Skendros P, Chrysanthopoulou A, Rousset F, Kambas K, Arampatzioglou A, Mitsios A, Bocly V, Konstantinidis T, Pellet P, Angelidou I, Apostolidou E, Ritis D, Tsironidou V, Galtsidis S, Papagoras C, Stakos D, Kouklakis G, Dalla V, Koffa M, Mitroulis I, Theodorou I, Ritis K Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1beta-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps. J Allergy Clin Immunol 2017; 140(5):1378–1387 e13.

  95. Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997;72(7):611–5.

    Article  CAS  PubMed  Google Scholar 

  96. Mistry P, Carmona-Rivera C, Ombrello AK, Hoffmann P, Seto NL, Jones A, et al. Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome. Ann Rheum Dis. 2018;77(12):1825–33.

    Article  CAS  PubMed  Google Scholar 

  97. Frank MB, Wang S, Aggarwal A, Knowlton N, Jiang K, Chen Y, et al. Disease-associated pathophysiologic structures in pediatric rheumatic diseases show characteristics of scale-free networks seen in physiologic systems: implications for pathogenesis and treatment. BMC Med Genet. 2009;2:9.

    CAS  Google Scholar 

  98. Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G. Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clin Exp Immunol. 2014;177(1):134–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Duvvuri B, Pachman LM, Morgan G, Khojah AM, Klein-Gitelman M, Curran ML, et al. Neutrophil extracellular traps in tissue and periphery in juvenile dermatomyositis. Arthritis Rheumatol. 2020;72(2):348–58.

    Article  CAS  PubMed  Google Scholar 

  100. Peng Y, Zhang S, Zhao Y, Liu Y, Yan B. Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis. Clin Rheumatol. 2018;37(1):107–15.

    Article  PubMed  Google Scholar 

  101. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138–49.

    Article  PubMed  Google Scholar 

  102. Hu X, Xie Q, Mo X, Jin Y. The role of extracellular histones in systemic-onset juvenile idiopathic arthritis. Ital J Pediatr. 2019;45(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Torres-Ruiz J, Carrillo-Vazquez DA, Tapia-Rodriguez M, Garcia-Galicia JA, Alcocer-Varela J, Gomez-Martin D. The role of low density granulocytes and NETosis in the pathogenesis of adult-onset Still’s disease. Clin Exp Rheumatol. 2019; 37 Suppl 121(6):74–82.

  104. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Iwaki-Egawa S, Yamamoto T, Watanabe Y. Human plasma adenosine deaminase 2 is secreted by activated monocytes. Biol Chem. 2006;387(3):319–21.

    Article  CAS  PubMed  Google Scholar 

  106. Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O’Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134(4):395–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhao ML, Chi H, Sun L. Neutrophil extracellular traps of Cynoglossus semilaevis: production characteristics and antibacterial effect. Front Immunol. 2017;8:290.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Rheumatology, Department of Pediatrics, Jim Pattison Children’s Hospital, University of Saskatchewan, Saskatoon, SK, Canada

    Mehul P. Jariwala

  2. Departments of Pediatrics and Medicine, Division of Rheumatology, The Hospital for Sick Children, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

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  1. Mehul P. Jariwala
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  2. Ronald M. Laxer
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Correspondence to Mehul P. Jariwala.

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Jariwala, M.P., Laxer, R.M. NETosis in Rheumatic Diseases. Curr Rheumatol Rep 23, 9 (2021). https://doi.org/10.1007/s11926-020-00977-6

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