High mobility group box 1 in women with unexplained recurrent pregnancy loss
-
Carlo Ticconi
, Stefania Mardente
, Emanuela Mari
, Alessandro Mauriello
, Giuseppe Rizzo
and Alessandra Zicari
Abstract
Objectives
To investigate whether high mobility group box 1 (HMGB1) is involved in unexplained recurrent pregnancy loss (uRPL).
Methods
Plasma levels of HMGB1 were measured by ELISA in non-pregnant women with (n=44) and without (n=53 controls) uRPL. Their platelets and plasma-derived microvesicles (MVs) were also assayed for HMGB1. Endometrial biopsies were taken in selected uRPL (n=5) and control women (n=5) and the tissue expression of HMGB1 was determined by western blot and immunohistochemistry (IHC).
Results
plasma levels of HMGB1 were significantly higher in women with uRPL than in control women. HMGB1 content in platelets and MVs obtained from women with uRPL was significantly higher than that obtained from control women. HMGB1 expression in endometrium was higher in tissues obtained from women with uRPL than in tissues obtained from control women. IHC analysis revealed that HMGB1 is expressed in endometrium with different patterns between uRPL and control women.
Conclusions
HMGB1 could be involved in uRPL.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The study was approved by the Institutional Review Board (IRB) of Policlinico Tor Vergata University Hospital (protocol number: 242/21).
References
1. Practice Committee of the American Society for Reproductive Medicine. Practice Committee of the American Society for Reproductive Medicine: definition of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013;99:63. https://doi.org/10.1016/j.fertnstert.2012.09.023.Search in Google Scholar PubMed
2. Recurrent pregnancy loss: guideline of the European society of human reproduction and Embryology. ESHRE early pregnancy guideline development group. 2017: 1–153. Available at: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.aspx.Search in Google Scholar
3. Garrido-Gimenez, C, Alijotas-Reig, J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med 2015;91:151–62. https://doi.org/10.1136/postgradmedj-2014-132672.Search in Google Scholar PubMed
4. El Hachem, H, Crepaux, V, May-Panloup, P, Descamps, P, Legendre, G, Bouet, PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health 2017;9:331–45. https://doi.org/10.2147/ijwh.s100817.Search in Google Scholar
5. Kutteh, WH. Novel strategies for the management of recurrent pregnancy loss. Semin Reprod Med 2015;3:161–8. https://doi.org/10.1055/s-0035-1552586.Search in Google Scholar PubMed
6. Robertson, SA, Moldenhauer, LM. Immunological determinants of implantation success. Int J Dev Biol 2014;58:205–17. https://doi.org/10.1387/ijdb.140096sr.Search in Google Scholar PubMed
7. Roberton, SA, Care, AS, Moldenhauer, LM. Regulatory T cells in embryo implantation and the immune response to pregnancy. J Clin Invest 2018;128:4224–35. https://doi.org/10.1172/jci122182.Search in Google Scholar PubMed PubMed Central
8. Schumacher, A, Sharkey, DJ, Robertson, SA, Zenclussen, AC. Immune cells at the fetomaternal interface: how the microenvironment modulates immune cells to foster fetal development. J Immunol 2018;201:325–34. https://doi.org/10.4049/jimmunol.1800058.Search in Google Scholar PubMed
9. PrabhuDas, M, Bonney, E, Caron, K, Dey, S, Erlebacher, A, Fazleabas, A, et al.. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol 2015;16:328–34. https://doi.org/10.1038/ni.3131.Search in Google Scholar PubMed PubMed Central
10. Kwak-Kim, J, Bao, S, Lee, SK, Kim, JW, Gilman-Sachs, A. Immunological modes of pregnancy loss: inflammation, immune effectors, and stress. Am J Reprod Immunol 2014;72:129–40. https://doi.org/10.1111/aji.12234.Search in Google Scholar PubMed
11. El-Azzamy, H, Dambaeva, SV, Katukurundage, D, Salazar Garcia, MD, Skariah, A, Hussein, Y, et al.. Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses. Am J Reprod Immunol 2018;80:e13024. https://doi.org/10.1111/aji.13024.Search in Google Scholar PubMed
12. Kamoi, M, Fukui, A, Kwak-Kim, J, Fuchinoue, K, Funamizu, A, Chiba, H, et al.. NK22 cells in the uterine mid-secretory endometrium and peripheral blood of women with recurrent pregnancy loss and unexplained infertility. Am J Reprod Immunol 2015;73:557–67. https://doi.org/10.1111/aji.12356.Search in Google Scholar PubMed
13. Teklenburg, G, Salker, M, Molokhia, M, Lavery, S, Trew, G, Aojanepong, T, et al.. Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS One 2010;5:e10258. https://doi.org/10.1371/journal.pone.0010258.Search in Google Scholar PubMed PubMed Central
14. Dong, P, Wen, X, Liu, J, Yan, CY, Yuan, J, Luo, LR, et al.. Simultaneous detection of decidual Th1/Th2 and NK1/NK2 immunophenotyping in unknown recurrent miscarriage using 8-color flow cytometry with FSC/Vt extended strategy. Biosci Rep 2017;3:BSR20170150. https://doi.org/10.1042/bsr20170150.Search in Google Scholar PubMed PubMed Central
15. Ticconi, C, Pietropolli, A, Di Simone, N, Piccione, E, Fazleabas, A. Endometrial immune dysfunction in recurrent pregnancy loss. Int J Mol Sci 2019;20:E5332. https://doi.org/10.3390/ijms20215332.Search in Google Scholar PubMed PubMed Central
16. Kang, R, Chen, R, Zhang, Q, Hou, W, Wu, S, Cao, L, et al.. HMGB1 in health and disease. Mol Aspect Med 2014;40:1–116. https://doi.org/10.1016/j.mam.2014.05.001.Search in Google Scholar PubMed PubMed Central
17. Sapojnikova, N, Maman, J, Myers, FA, Thorne, AW, Vorobyev, VI, Crane-Robinson, C. Biochemical observation of the rapid mobility of nuclear HMGB1. Biochim Biophys Acta 2005;1729:57–63. https://doi.org/10.1016/j.bbaexp.2005.03.002.Search in Google Scholar PubMed
18. Gorgulho, CM, Romagnoli, GG, Bharthi, R, Lotze, MT. Johnny on the spot-chronic inflammation is driven by HMGB1. Front Immunol 2019;10:1561. https://doi.org/10.3389/fimmu.2019.01561.Search in Google Scholar PubMed PubMed Central
19. Zicari, A, Centonze, C, Realacci, M, Buchetti, B, Pietropolli, A, Ticconi, C. Estradiol 17-beta and progesterone modulate inducible nitric oxide synthase and high mobility group box 1 expression in human endometrium. Reprod Sci 2008;15:559–66. https://doi.org/10.1177/1933719107312560.Search in Google Scholar PubMed
20. Zenerino, C, Nuzzo, AM, Giuffrida, D, Biolcati, M, Zicari, A, Todros, T, et al.. The HMGB1/RAGE pro-inflammatory axis in the human placenta: modulating effect of low molecular weight heparin. Molecules 2017;22:1997. https://doi.org/10.3390/molecules22111997.Search in Google Scholar PubMed PubMed Central
21. Ticconi, C, Zicari, A, Belmonte, A, Realacci, M, Rao, CV, Piccione, E. Pregnancy-promoting actions of HCG in human myometrium and fetal membranes placenta. 2007;28:S137–43, https://doi.org/10.1016/j.placenta.2007.01.002.Search in Google Scholar PubMed
22. Hu, Y, Yan, R, Zhang, C, Zhou, Z, Liu, M, Wang, C, et al.. High-Mobility group box 1 from hypoxic trophoblasts promotes endothelial microparticle production and thrombophilia in preeclampsia. Arterioscler Thromb Vasc Biol 2018;38:1381–91. https://doi.org/10.1161/atvbaha.118.310940.Search in Google Scholar PubMed PubMed Central
23. Shao, J, Zhao, M, Tong, M, Wei, J, Wise, MR, Stone, P, et al.. Increased levels of HMGB1 in trophoblastic debris may contribute to preeclampsia. Reproduction 2016;152:775–84. https://doi.org/10.1530/rep-16-0083.Search in Google Scholar
24. Plazyo, O, Romero, R, Unkel, R, Balancio, A, Mial, TN, Xu, Y, et al.. HMGB1 induces an inflammatory response in the chorioamniotic membranes that is partially mediated by the inflammasome. Biol Reprod 2016;95:130. https://doi.org/10.1095/biolreprod.116.144139.Search in Google Scholar PubMed PubMed Central
25. Yan, H, Zhu, L, Zhang, Z, Li, H, Li, P, Wang, Y, et al.. HMGB1-RAGE signaling pathway in pPROM. Taiwan J Obstet Gynecol 2018;57:211–6. https://doi.org/10.1016/j.tjog.2018.02.008.Search in Google Scholar PubMed
26. Xie, H, Qiao, P, Lu, Y, Li, Y, Tang, Y, Huang, Y, et al.. Increased expression of high mobility group box protein 1 and vascular endothelial growth factor in placenta previa. Mol Med Rep 2017;16:9051–9. https://doi.org/10.3892/mmr.2017.7682.Search in Google Scholar PubMed
27. Santangelo, C, Filardi, T, Perrone, G, Mariani, M, Mari, E, Scazzocchio, B, et al.. Cross-talk between fetal membranes and visceral adipose tissue involves HMGB1-RAGE and VIP-VPAC2 pathways in human gestational diabetes mellitus. Acta Diabetol 2019;56:681–9. https://doi.org/10.1007/s00592-019-01304-xSearch in Google Scholar PubMed
28. Bruno, V, Ticconi, C, Martelli, F, Nuccetelli, M, Capogna, MV, Sorge, R, et al.. Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study. BMC Pregnancy Childbirth 2020;20:44–6. https://doi.org/10.1186/s12884-020-2724-6.Search in Google Scholar PubMed PubMed Central
29. Ticconi, C, Pietropolli, A, D’Ippolito, S, Chiaramonte, C, Piccione, E, Scambia, G, et al.. Time-to-pregnancy in women with unexplained recurrent pregnancy loss: a controlled study. Reprod Sci 2020;27:1121–8. https://doi.org/10.1007/s43032-019-00122-4.Search in Google Scholar PubMed
30. Guarino, ML, Massimi, I, Mardente, S, Lappa, A, Donfrancesco, S, Visentin, GP, et al.. New platelet functional method for identification of pathogenic antibodies in HIT patients. Platelets 2017;28:728–30. https://doi.org/10.1080/09537104.2017.1293803.Search in Google Scholar PubMed
31. Mardente, S, Mari, E, Massimi, I, Tafani, M, Guerriero, R, Morsilli, O, et al.. From human megakaryocytes to platelets: effects of aspirin on high-mobility group box 1/receptor for advanced glycation end products Axis. Front Immunol 2018;8. https://doi.org/10.3389/fimmu.2017.01946.Search in Google Scholar PubMed PubMed Central
32. Strug, MR, Su, RW, Kim, TH, Mauriello, A, Ticconi, C, Lessey, BA, et al.. RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. FASEB J 2018;32:2452–66. https://doi.org/10.1096/fj.201701032r.Search in Google Scholar PubMed PubMed Central
33. Kowal, EJK, Ter-Ovanesyan, D, Regev, A, Church, GM. Extracellular vesicle isolation and analysis by western blotting. In: Kuo, W, Jia, S, editors Extracellular vesicles. methods in molecular biology, vol 1660. New York: Humana Press; 2017.10.1007/978-1-4939-7253-1_12Search in Google Scholar PubMed
34. Wang, K, Yang, ZQ, Yu, HF, Wang, YS, Guo, B, Yue, ZP. High mobility group box 1 regulates uterine decidualization through bone morphogenetic protein 2 and plays a role in kruppel-like factor 5-induced stromal differentiation. Cell Physiol Biochem 2018;48:2399–408. https://doi.org/10.1159/000492655.Search in Google Scholar PubMed
35. Shirasuna, K, Seno, K, Ohtsu, A, Shiratsuki, S, Ohkuchi, A, Suzuki, H, et al.. AGEs and HMGB1 increase inflammatory cytokine production from human placental cells, resulting in an enhancement of monocyte migration. Am J Reprod Immunol 2016;75:557–68. https://doi.org/10.1111/aji.12506.Search in Google Scholar PubMed
36. Holmlund, U, Wähämaa, H, Bachmayer, N, Bremme, K, Sverremark-Ekström, E, Palmblad, K. The novel inflammatory cytokine high mobility group box protein 1 (HMGB1) is expressed by human term placenta. Immunology 2007;122:430–7. https://doi.org/10.1111/j.1365-2567.2007.02662.x.Search in Google Scholar PubMed PubMed Central
37. Giacobbe, A, Granese, R, Grasso, R, Salpietro, V, Corrado, F, Giorgianni, G, et al.. Association between maternal serum high mobility group box 1 levels and pregnancy complicated by gestational diabetes mellitus. Nutr Metabol Cardiovasc Dis 2016;26:414–8. https://doi.org/10.1016/j.numecd.2016.02.007.Search in Google Scholar PubMed
38. Brien, ME, Baker, B, Duval, C, Gaudreault, V, Jones, RL, Girard, S. Alarmins at the maternal-fetal interface: involvement of inflammation in placental dysfunction and pregnancy complications. Can J Physiol Pharmacol 2019;97:206–12. https://doi.org/10.1139/cjpp-2018-0363.Search in Google Scholar PubMed
39. Gomez-Lopez, N, Romero, R, Plazyo, O, Panaitescu, B, Furcron, AE, Miller, D, et al.. Intra-amniotic administration of HMGB1 induces spontaneous preterm labor and birth. Am J Reprod Immunol 2016;75:3–7. https://doi.org/10.1111/aji.12443.Search in Google Scholar PubMed PubMed Central
40. Bhutada, S, Basak, T, Savardekar, L, Katkam, RR, Jadhav, G, Metkari, SM, et al.. High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. Hum Reprod 2014;29:763–80. https://doi.org/10.1093/humrep/det461.Search in Google Scholar PubMed
41. Jin, H, Wu, J, Yang, Q, Cai, Y, He, W, Liu, C. High mobility group box 1 protein polymorphism affects susceptibility to recurrent pregnancy loss by up-regulating gene expression in chorionic villi. J Assist Reprod Genet 2015;32:1123–8. https://doi.org/10.1007/s10815-015-0493-3.Search in Google Scholar PubMed PubMed Central
42. Zou, H, Yin, J, Zhang, Z, Xiang, H, Wang, J, Zhu, D, et al.. Destruction in maternal-fetal interface of URSA patients via the increase of the HMGB1-RAGE/TLR2/TLR4-NF-κB signaling pathway. Life Sci 2020;250:117543. https://doi.org/10.1016/j.lfs.2020.117543.Search in Google Scholar PubMed
43. Mendonça Gorgulho, C, Murthy, P, Liotta, L, Espina, V, Lotze, MT. Different measures of HMGB1 location in cancer immunology. Methods Enzymol 2019;629:195–217. https://doi.org/10.1016/bs.mie.2019.10.011.Search in Google Scholar PubMed
44. Aikawa, S, Deng, W, Liang, X, Yuan, J, Bartos, A, Sun, X, et al.. Uterine deficiency of high-mobility group box-1 (HMGB1) protein causes implantation defects and adverse pregnancy outcomes. Cell Death Differ 2020;27:1489–504. https://doi.org/10.1038/s41418-019-0429-z.Search in Google Scholar PubMed PubMed Central
45. Bonaldi, T, Talamo, F, Scaffidi, P, Ferrera, D, Porto, A, Bachi, A, et al.. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 2003;22:5551–60. https://doi.org/10.1093/emboj/cdg516.Search in Google Scholar PubMed PubMed Central
© 2023 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Obituary
- A tribute to Professor Moshe Mazor, M.D.
- Mini Review
- Systematic review of the long-term effects of postnatal corticosteroids
- Opinion Paper
- The proposal of the novel fetal shoulder dystocia graduation: a clinical-based opinion
- Corner of Academy
- Prenatal diagnosis of bilobate placenta: incidence, risk factors and impact on pregnancy outcomes
- Original Articles – Obstetrics
- High mobility group box 1 in women with unexplained recurrent pregnancy loss
- Velamentous cord insertion in monochorionic twin pregnancies: a step forward in screening for twin to twin transfusion syndrome and birthweight discordance?
- Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM)
- Perinatal, obstetric and parental risk factors for asthma in the offspring throughout childhood: a longitudinal cohort study
- Increased risk of severe COVID-19 in pregnancy in a multicenter propensity score-matched study
- Comparative clinical and placental pathologic characteristics in pregnancies with and without SARS-CoV-2 infection
- An analysis of factors affecting survival in prenatally diagnosed omphalocele
- The impact of abnormal maternal body mass index during pregnancy on perinatal outcomes: a registry-based study from Qatar
- Original Articles – Fetus
- Embryonic and fetal tiny pericardial fluid collections at less than 12 weeks of gestation
- Modeling fetal cortical development by quantile regression for gestational age and head circumference: a prospective cross sectional study
- The effect of 50 GR oral glucose tolerance test on fetal celiac artery and superior mesenteric artery Doppler parameters in healthy pregnancies
- Original Articles – Neonates
- Carboxyhaemoglobin levels in infants with hypoxic ischaemic encephalopathy
- Exploring professionals’ views regarding prenatal counselling in congenital diaphragmatic hernia
- Letter to the Editor
- Cutting of the strangulated double nuchal umbilical cord in a release of the severe shoulder dystocia: forensically justified or controversial procedure
- Retraction
- Retraction of: Pre-operative tranexemic acid vs. etamsylate in reducing blood loss during elective cesarean section: randomized controlled trial
- Retraction of: Lidocaine vs. tramadol vs. placebo wound infiltration for post-cesarean section pain relief: a randomized controlled trial
Articles in the same Issue
- Frontmatter
- Obituary
- A tribute to Professor Moshe Mazor, M.D.
- Mini Review
- Systematic review of the long-term effects of postnatal corticosteroids
- Opinion Paper
- The proposal of the novel fetal shoulder dystocia graduation: a clinical-based opinion
- Corner of Academy
- Prenatal diagnosis of bilobate placenta: incidence, risk factors and impact on pregnancy outcomes
- Original Articles – Obstetrics
- High mobility group box 1 in women with unexplained recurrent pregnancy loss
- Velamentous cord insertion in monochorionic twin pregnancies: a step forward in screening for twin to twin transfusion syndrome and birthweight discordance?
- Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM)
- Perinatal, obstetric and parental risk factors for asthma in the offspring throughout childhood: a longitudinal cohort study
- Increased risk of severe COVID-19 in pregnancy in a multicenter propensity score-matched study
- Comparative clinical and placental pathologic characteristics in pregnancies with and without SARS-CoV-2 infection
- An analysis of factors affecting survival in prenatally diagnosed omphalocele
- The impact of abnormal maternal body mass index during pregnancy on perinatal outcomes: a registry-based study from Qatar
- Original Articles – Fetus
- Embryonic and fetal tiny pericardial fluid collections at less than 12 weeks of gestation
- Modeling fetal cortical development by quantile regression for gestational age and head circumference: a prospective cross sectional study
- The effect of 50 GR oral glucose tolerance test on fetal celiac artery and superior mesenteric artery Doppler parameters in healthy pregnancies
- Original Articles – Neonates
- Carboxyhaemoglobin levels in infants with hypoxic ischaemic encephalopathy
- Exploring professionals’ views regarding prenatal counselling in congenital diaphragmatic hernia
- Letter to the Editor
- Cutting of the strangulated double nuchal umbilical cord in a release of the severe shoulder dystocia: forensically justified or controversial procedure
- Retraction
- Retraction of: Pre-operative tranexemic acid vs. etamsylate in reducing blood loss during elective cesarean section: randomized controlled trial
- Retraction of: Lidocaine vs. tramadol vs. placebo wound infiltration for post-cesarean section pain relief: a randomized controlled trial