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Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia?

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Abstract

Recent studies have suggested that the innate immune system is involved in the pathogenesis of preeclampsia. Its pathogenesis involves neutrophil activation and increased levels of cell-free DNA in the maternal plasma. Activation of neutrophils has recently been shown to induce DNA containing neutrophil extracellular traps (NETs) which trap and kill bacteria. Massive NETs induction by the placentally derived factors (IL-8 and placental micro-debris) and their increased presence in preeclamptic placenta suggest that NETs might be involved in the pathogenesis of preeclampsia. Therefore, increased presence of NETs in preeclampsia may play a role in the deficient placental perfusion associated with this disorder.

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References

  1. Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594

    Article  PubMed  CAS  Google Scholar 

  2. Borzychowski AM, Sargent IL, Redman CW (2006) Inflammation and pre-eclampsia. Semin Fetal Neonatal Med 11:309–316

    Article  PubMed  CAS  Google Scholar 

  3. Sacks G, Sargent I, Redman C (1999) An innate view of human pregnancy. Immunol Today 20:114–118

    Article  PubMed  CAS  Google Scholar 

  4. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CW (2003) Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol 59:153–160

    Article  PubMed  CAS  Google Scholar 

  5. Redman CW, Sargent IL (2004) Preeclampsia and the systemic inflammatory response. Semin Nephrol 24:565–570

    Article  PubMed  Google Scholar 

  6. Huppertz B, Kingdom J, Caniggia I, Desoye G, Black S, Korr H, Kaufmann P (2003) Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta 24:181–190

    Article  PubMed  CAS  Google Scholar 

  7. Knight M, Redman CW, Linton EA, Sargent IL (1998) Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol 105:632–640

    PubMed  CAS  Google Scholar 

  8. Smarason AK, Sargent IL, Starkey PM, Redman CW (1993) The effect of placental syncytiotrophoblast microvillous membranes from normal and pre-eclamptic women on the growth of endothelial cells in vitro. Br J Obstet Gynaecol 100:943–949

    PubMed  CAS  Google Scholar 

  9. Gupta AK, Rusterholz C, Huppertz B, Malek A, Schneider H, Holzgreve W, Hahn S (2005) A comparative study of the effect of three different syncytiotrophoblast micro-particles preparations on endothelial cells. Placenta 26:59–66

    Article  PubMed  CAS  Google Scholar 

  10. Cockell AP, Learmont JG, Smarason AK, Redman CW, Sargent IL, Poston L (1997) Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function. Br J Obstet Gynaecol 104:235–240

    PubMed  CAS  Google Scholar 

  11. Barden A, Graham D, Beilin LJ, Ritchie J, Baker R, Walters BN, Michael CA (1997) Neutrophil CD11B expression and neutrophil activation in pre-eclampsia. Clin Sci (Lond) 92:37–44

    CAS  Google Scholar 

  12. Clark P, Boswell F, Greer IA (1998) The neutrophil and preeclampsia. Semin Reprod Endocrinol 16:57–64

    PubMed  CAS  Google Scholar 

  13. Aly AS, Khandelwal M, Zhao J, Mehmet AH, Sammel MD, Parry S (2004) Neutrophils are stimulated by syncytiotrophoblast microvillous membranes to generate superoxide radicals in women with preeclampsia. Am J Obstet Gynecol 190:252–258

    Article  PubMed  CAS  Google Scholar 

  14. Tsukimori K, Maeda H, Ishida K, Nagata H, Koyanagi T, Nakano H (1993) The superoxide generation of neutrophils in normal and preeclamptic pregnancies. Obstet Gynecol 81:536–540

    PubMed  CAS  Google Scholar 

  15. Gryglewski RJ, Palmer RM, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456

    Article  PubMed  CAS  Google Scholar 

  16. Holzgreve W, Ghezzi F, Di Naro E, Ganshirt D, Maymon E, Hahn S (1998) Disturbed feto-maternal cell traffic in preeclampsia. Obstet Gynecol 91:669–672

    Article  PubMed  CAS  Google Scholar 

  17. Lo YM, Lau TK, Zhang J, Leung TN, Chang AM, Hjelm NM, Elmes RS, Bianchi DW (1999) Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin Chem 45:1747–1751

    PubMed  CAS  Google Scholar 

  18. Zhong XY, Laivuori H, Livingston JC, Ylikorkala O, Sibai BM, Holzgreve W, Hahn S (2001) Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol 184:414–419

    Article  PubMed  CAS  Google Scholar 

  19. Swinkels DW, de Kok JB, Hendriks JC, Wiegerinck E, Zusterzeel PL, Steegers EA (2002) Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum. Clin Chem 48:650–653

    PubMed  CAS  Google Scholar 

  20. Leung TN, Zhang J, Lau TK, Chan LY, Lo YM (2001) Increased maternal plasma fetal DNA concentrations in women who eventually develop preeclampsia. Clin Chem 47:137–139

    PubMed  CAS  Google Scholar 

  21. Zhong XY, Holzgreve W, Hahn S (2002) The levels of circulatory cell free fetal DNA in maternal plasma are elevated prior to the onset of preeclampsia. Hypertens Pregnancy 21:77–83

    Article  PubMed  CAS  Google Scholar 

  22. Levine RJ, Qian C, Leshane ES, Yu KF, England LJ, Schisterman EF, Wataganara T, Romero R, Bianchi DW (2004) Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia. Am J Obstet Gynecol 190:707–713

    Article  PubMed  CAS  Google Scholar 

  23. Hahn S, Holzgreve W (2002) Fetal cells and cell-free fetal DNA in maternal blood: new insights into pre-eclampsia. Hum Reprod Update 8:501–508

    Article  PubMed  CAS  Google Scholar 

  24. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535

    Article  PubMed  CAS  Google Scholar 

  25. Wartha F, Beiter K, Normark S, Henriques-Normark B (2007) Neutrophil extracellular traps: casting the NET over pathogenesis. Curr Opin Microbiol 10:52–56

    Article  PubMed  CAS  Google Scholar 

  26. Urban CF, Reichard U, Brinkmann V, Zychlinsky A (2006) Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 8:668–676

    Article  PubMed  CAS  Google Scholar 

  27. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V (2006) DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396–400

    Article  PubMed  CAS  Google Scholar 

  28. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B (2006) An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol 16:401–407

    Article  PubMed  CAS  Google Scholar 

  29. Lippolis JD, Reinhardt TA, Goff JP, Horst RL (2006) Neutrophil extracellular trap formation by bovine neutrophils is not inhibited by milk. Vet Immunol Immunopathol 113:248–255

    Article  PubMed  CAS  Google Scholar 

  30. Lee WL, Grinstein S (2004) Immunology. The tangled webs that neutrophils weave. Science 303:1477–1478

    Article  PubMed  CAS  Google Scholar 

  31. Gupta AK, Hasler P, Holzgreve W, Gebhardt S, Hahn S (2005) Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum Immunol 66:1146–1154

    Article  PubMed  CAS  Google Scholar 

  32. Huppertz B, Kingdom JC (2004) Apoptosis in the trophoblast—role of apoptosis in placental morphogenesis. J Soc Gynecol Investig 11:353–362

    Article  PubMed  CAS  Google Scholar 

  33. Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun SH, Fisher SJ (1997) Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 151:1809–1818

    PubMed  CAS  Google Scholar 

  34. Roberts JM, Hubel CA (2004) Oxidative stress in preeclampsia. Am J Obstet Gynecol 190:1177–1178

    Article  PubMed  Google Scholar 

  35. Canas PE (1999) The role of xanthine oxidase and the effects of antioxidants in ischemia reperfusion cell injury. Acta Physiol Pharmacol Ther Latinoam 49:13–20

    PubMed  CAS  Google Scholar 

  36. Zweier JL, Talukder MA (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70:181–190

    Article  PubMed  CAS  Google Scholar 

  37. Bowen RS, Gu Y, Zhang Y, Lewis DF, Wang Y (2005) Hypoxia promotes interleukin-6 and -8 but reduces interleukin-10 production by placental trophoblast cells from preeclamptic pregnancies. J Soc Gynecol Investig 12:428–432

    Article  PubMed  CAS  Google Scholar 

  38. Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 186:158–166

    Article  PubMed  Google Scholar 

  39. Lo YM, Leung TN, Tein MS, Sargent IL, Zhang J, Lau TK, Haines CJ, Redman CW (1999) Quantitative abnormalities of fetal DNA in maternal serum in preeclampsia. Clin Chem 45:184–188

    PubMed  CAS  Google Scholar 

  40. Zhong XY, Holzgreve W, Hahn S (2001) Circulatory fetal and maternal DNA in pregnancies at risk and those affected by preeclampsia. Ann N Y Acad Sci 945:138–140

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Mr. Daniel Mathys (ZMB, University of Basel) for his excellent technical assistance with the scanning electron microscopy and Mrs. Vivian Kiefer-Vargas and Mrs. Lisbeth Dudler for their kind help in the preparation of specimens for microscopic analysis. We would also like to thank Dr. Susanne Gatfield for her help with fluorescence microscopy and Dr. Carolyn Troeger for placentae collection.

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Authors and Affiliations

  1. Laboratory for Prenatal Medicine, University Women’s Hospital/Department of Research, University Hospital, Hebelstrasse 20, CH-4031, Basel, Switzerland

    Anurag Kumar Gupta, Wolfgang Holzgreve & Sinuhe Hahn

  2. Department of Rheumatology, Kantonsspital Aarau, Aargau, Switzerland

    Paul Hasler

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  1. Anurag Kumar Gupta
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  2. Paul Hasler
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  3. Wolfgang Holzgreve
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  4. Sinuhe Hahn
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Correspondence to Anurag Kumar Gupta.

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Gupta, A.K., Hasler, P., Holzgreve, W. et al. Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia?. Semin Immunopathol 29, 163–167 (2007). https://doi.org/10.1007/s00281-007-0073-4

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  • DOI: https://doi.org/10.1007/s00281-007-0073-4

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