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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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Li, Min; Piao, Longzhu; Chen, Chie-Pein et al. (2016) Modulation of Decidual Macrophage Polarization by Macrophage Colony-Stimulating Factor Derived from First-Trimester Decidual Cells: Implication in Preeclampsia. Am J Pathol 186:1258-66
Chen, Chie-Pein; Piao, Longzhu; Chen, Xilin et al. (2015) Expression of Interferon ? by Decidual Cells and Natural Killer Cells at the Human Implantation Site: Implications for Preeclampsia, Spontaneous Abortion, and Intrauterine Growth Restriction. Reprod Sci 22:1461-7
Piao, L; Chen, C-P; Yeh, C-C et al. (2015) Chinese herbal medicine for miscarriage affects decidual micro-environment and fetal growth. Placenta 36:559-66
Lockwood, Charles J; Basar, Murat; Kayisli, Umit A et al. (2014) Interferon-? protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia. Am J Pathol 184:2549-59
Yeh, Chang-Ching; Chao, Kuan-Chong; Huang, S Joseph (2013) Innate immunity, decidual cells, and preeclampsia. Reprod Sci 20:339-53
Lockwood, Charles J; Huang, S Joseph; Chen, Chie-Pein et al. (2013) Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol 183:841-56
Wu, Z M; Yang, H; Li, M et al. (2012) Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts. Placenta 33:188-94
Li, Min; Wu, Zhen-Ming; Yang, Hui et al. (2011) NFýýB 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. J Clin Endocrinol Metab 96:2502-11
Huang, S Joseph; Zenclussen, Ana C; Chen, Chie-Pein et al. (2010) The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia. Am J Pathol 177:2472-82
Duzyj, Christina M; Barnea, Eytan R; Li, Min et al. (2010) Preimplantation factor promotes first trimester trophoblast invasion. Am J Obstet Gynecol 203:402.e1-4

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