The Role of Decidual Innate Immunity in the Pathogenesis of Preeclampsia

Summary

Principal Investigator: SE TE HUANG
Affiliation: Yale University
Country: USA
Abstract: Implanting human cytotrophoblasts (CTBs) invade an underlying decidua comprised of decidual cells and such immune cells as macrophages (MFs) and dendritic cells (DCs). These specialized antigen-presenting cells (APCs) mediate innate immunity, subsequent activation of the adaptive immune system and in the development of immune tolerance. Perturbation of the balance between defense against pathogens and tolerance of the semi-allogeneic embryo in the decidua contributes to preeclampsia-toxemia (PET), a leading cause of perinatal and maternal morbidity and mortality. PET is associated with an aberrant maternal immune response that restricts CTB invasion and leads to impaired remodeling of the spiral arteries into large bore low resistance vessels necessary to increase uterine blood flow to the developing feto-placental unit. In support of the hypothesis that an excess influx and activation of MFs and DCs impair CTB invasion and promotes PET, we observed a marked excess of MFs and DCs in preeclamptic decidua. In leukocyte-free first trimester decidual cells, we found that the pro-inflammatory cytokines, tumor necrosis factor-a (TNF-1) and interleukin-1 beta (IL-12), profoundly enhanced expression of macrophage-colony stimulating factor (M-CSF), granulocyte- macrophage-colony stimulating factor (GM-CSF), which activate immature MFs and DCs to mature MFs and DCs as well as an array of monocyte/macrophage- and DC-recruiting chemokines. We also found that the direct inhibition of CTB invasion by macrophages was enhanced by conditioned media from IL-12-treated decidual cell culture. Our central hypothesis is that pro-inflammatory cytokines dysregulate trafficking and activation of APCs by targeting decidual cells and, thus, contribute to the immune modulation and the development of PET. To test this hypothesis, we will 1) identify those chemokines responsible for recruiting APCs using immune cell migration assays;2) determine whether M-CSF and GM-CSF play roles in activating APCs by examining effector molecules, activation markers and functional assays for antigen-presenting activity;3) elucidate the effects of TNF-1 - or IL-12 -treated decidual cells on CTB invasion and vascular remodeling using co-culture of CTBs, APCs and endothelial cells;4) use a novel MF- or DC-depleted PET mouse model to evaluate the effects of activated APCs on the development of PET. This work will lead to better understanding of the pathogenesis of PET and the development of effective prevention and therapies to combat PET. Consequently, stress and financial burden for affected family and society will be significantly reduced. PUBLIC HEALTH RELEVANCE: Preeclampsia is a multi-system disorder that complicates 5% to 10% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality worldwide. This study of the immunological basis of preeclampsia will result in new therapies to combat this complication during pregnancy. Hence, the welfare of affected families and society will be considerably improved.
Funding Period: 2008-04-01 - 2013-03-31
more information: NIH RePORT

Top Publications

  1. pmc Innate immunity, decidual cells, and preeclampsia
    Chang Ching Yeh
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Reprod Sci 20:339-53. 2013
  2. pmc Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia
    Charles J Lockwood
    Department of Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, Ohio, USA
    Am J Pathol 183:841-56. 2013
  3. pmc A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells
    Michael J Paidas
    Yale Women and Children s Center for Blood Disorders, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Am J Obstet Gynecol 202:459.e1-8. 2010
  4. pmc Preimplantation factor promotes first trimester trophoblast invasion
    Christina M Duzyj
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Women and Children s Center for Blood Disorders, New Haven, CT 06520 8063, USA
    Am J Obstet Gynecol 203:402.e1-4. 2010
  5. pmc Regulation of interleukin-6 expression in human decidual cells and its potential role in chorioamnionitis
    Charles J Lockwood
    Department of Obstetrics, Yale University School of Medicine, New Haven, Connecticut 06520 8063, USA
    Am J Pathol 177:1755-64. 2010
  6. pmc The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia
    S Joseph Huang
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, P O Box 208063, New Haven, CT 06520 8063, USA
    Am J Pathol 177:2472-82. 2010
  7. pmc NFκB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli
    Min Li
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, Connecticut 06520, USA
    J Clin Endocrinol Metab 96:2502-11. 2011
  8. pmc Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts
    Z M Wu
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, 333 Cedar St, P O Box 208063, New Haven, CT 06520, USA
    Placenta 33:188-94. 2012
  9. pmc Innate immunity, coagulation and placenta-related adverse pregnancy outcomes
    Min Li
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520 8063, USA
    Thromb Res 124:656-62. 2009

Scientific Experts

  • M J Paidas
  • Christina M Duzyj
  • S Joseph Huang
  • Min Li
  • Charles J Lockwood
  • Chang Ching Yeh
  • Z M Wu
  • Frederick Schatz
  • Lynn F Buchwalder
  • Umit Kayisli
  • Louise Koopman
  • Kuan Chong Chao
  • Dineke Smedts
  • Saeed Faramarzi
  • Jie Xu
  • Yingqun Huang
  • Ozlem Kayisli
  • Chie Pein Chen
  • C C Yeh
  • M Li
  • C J Lockwood
  • H Yang
  • W Di
  • F Schatz
  • Zhen Ming Wu
  • Hui Yang
  • Umit A Kayisli
  • William K Murk
  • Felice Arcuri
  • Arun Gopinath

Detail Information

Publications9

  1. pmc Innate immunity, decidual cells, and preeclampsia
    Chang Ching Yeh
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Reprod Sci 20:339-53. 2013
    ..Thus, this review will discuss the role of innate immunity and the potential contribution of decidual cells in the pathogenesis of PE...
  2. pmc Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia
    Charles J Lockwood
    Department of Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, Ohio, USA
    Am J Pathol 183:841-56. 2013
    ..Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia. ..
  3. pmc A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells
    Michael J Paidas
    Yale Women and Children s Center for Blood Disorders, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520 8063, USA
    Am J Obstet Gynecol 202:459.e1-8. 2010
    ..This study aims to elucidate PIF's effects in human endometrial stromal cells (HESC) decidualized by estrogen and progestin, which mimics the preimplantation milieu, and in first-trimester decidua cultures (FTDC)...
  4. pmc Preimplantation factor promotes first trimester trophoblast invasion
    Christina M Duzyj
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale Women and Children s Center for Blood Disorders, New Haven, CT 06520 8063, USA
    Am J Obstet Gynecol 203:402.e1-4. 2010
    ..Herein, we explore the effects of synthetic preimplantation factor on trophoblast invasion...
  5. pmc Regulation of interleukin-6 expression in human decidual cells and its potential role in chorioamnionitis
    Charles J Lockwood
    Department of Obstetrics, Yale University School of Medicine, New Haven, Connecticut 06520 8063, USA
    Am J Pathol 177:1755-64. 2010
    ..In conclusion, in situ and in vitro results indicate that significantly enhanced interleukin-6 expression levels in DCs during chorioamnionitis could be pivotal in skewing decidual monocyte differentiation to macrophages...
  6. pmc The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia
    S Joseph Huang
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, P O Box 208063, New Haven, CT 06520 8063, USA
    Am J Pathol 177:2472-82. 2010
    ....
  7. pmc NFκB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli
    Min Li
    Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, Connecticut 06520, USA
    J Clin Endocrinol Metab 96:2502-11. 2011
    ..IL-1β- or TNF-α-stimulated leukocyte-free first trimester decidual cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua...
  8. pmc Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts
    Z M Wu
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, 333 Cedar St, P O Box 208063, New Haven, CT 06520, USA
    Placenta 33:188-94. 2012
    ....
  9. pmc Innate immunity, coagulation and placenta-related adverse pregnancy outcomes
    Min Li
    Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520 8063, USA
    Thromb Res 124:656-62. 2009
    ..In this review, we will summarize the mutual regulation between blood coagulation and innate immune systems as well as their roles in the maintenance of normal pregnancy and in the pathogenesis of adverse pregnancy outcomes...