A fundamental feature of the immune system is to protect the host from foreign bodies and to promote tissue repair. These functions depend on the innate immune system's capacity to coordinate cell migration for surveillance and to recognize and respond to invading pathogens. The human decidua contains a large number of immune cells, such as macrophages, natural killer (NK) cells and regulatory T cells (Tregs). These, as well as decidual stromal cells, produce factors, necessary for the regulation of immune responses and placental development. The appropriate communication between all these cellular components at the maternal-fetal interface is critical for successful reproduction. Our general hypothesis is that during pregnancy, the trophoblast regulates leukocyte migration, differentiation and activation. In turn, the maternal immune system responds by producing factors that promote trophoblast survival and function. We propose that trophoblast cells recognize the uterine microenvironment and respond to it by recruiting immune cells necessary for a successful pregnancy. Moreover, we postulate that Toll-Like Receptors (TLR) mediate trophoblast recognition of this environment. Thus, our central hypothesis is that TLRs expressed by the trophoblast function as sensors of the maternal-fetal interface microenvironment which induce the production of cytokines/chemokines that will, in turn, regulate immune cell distribution and function. However, if the function of TLRs is left unchecked, the implantation site may become overwhelmed by immune activation. Therefore, TLR function and signaling must be tightly regulated in order to prevent pathologic conditions. Our objectives are to: 1) understand the function of TLRs in first trimester trophoblast cells;2) determine the effects of trophoblast TLR activation on maternal immune cells;3) characterize the regulatory mechanisms controlling TLR expression and function at the maternal-fetal interface;and 4) evaluate the role of TLRs in pregnancy outcome. Therefore, our specific aims are to:
Aim 1. Determine the cytokine profile in first trimester trophoblast cells following TLR activation.
Aim 2. Characterize the effect of trophoblast TLR activation on immune cell recruitment and function.
Aim 3. Study the regulation of TLR expression and function in trophoblast cells.
Aim 4. In vivo studies for the characterization TLR function in pregnancy.

Public Health Relevance

This proposal provides an alternative perspective on the role of the maternal immune system and its interactions with the trophoblast during pregnancy. Our studies will evaluate the supportive regulatory interactions between the trophoblast and the maternal immune system and investigate the role'of Toll-like receptors in these processes. As we learn more about the regulation of the expression and function of TLRs rlurinn nftnnannv wft will hotter understand thf>rftllular crosstalk ftxistinn at thfi matfirnal-fetal interface .

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-MCHG-B)
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Yale University
New Haven
United States
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Hoang, Mai; Potter, Julie A; Gysler, Stefan M et al. (2014) Human fetal membranes generate distinct cytokine profiles in response to bacterial Toll-like receptor and nod-like receptor agonists. Biol Reprod 90:39
Dekel, Nava; Gnainsky, Yulia; Granot, Irit et al. (2014) The role of inflammation for a successful implantation. Am J Reprod Immunol 72:141-7
Aldo, Paulomi B; Racicot, Karen; Craviero, Vinicius et al. (2014) Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 72:270-84
Racicot, Karen E; W√ľnsche, Vera; Auerbach, Ben et al. (2014) Human chorionic gonadotropin enhances trophoblast-epithelial interaction in an in vitro model of human implantation. Reprod Sci 21:1274-80
Racicot, Karen; Kwon, Ja-Young; Aldo, Paulomi et al. (2014) Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol 72:107-16
Kwon, Ja-Young; Romero, Roberto; Mor, Gil (2014) New insights into the relationship between viral infection and pregnancy complications. Am J Reprod Immunol 71:387-90
Bakaysa, S L; Potter, J A; Hoang, M et al. (2014) Single- and double-stranded viral RNA generate distinct cytokine and antiviral responses in human fetal membranes. Mol Hum Reprod 20:701-8
Abrahams, Vikki M; Potter, Julie A; Bhat, Geeta et al. (2013) Bacterial modulation of human fetal membrane Toll-like receptor expression. Am J Reprod Immunol 69:33-40
Racicot, Karen; Cardenas, Ingrid; Wunsche, Vera et al. (2013) Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol 191:934-41
Krikun, Graciela; Potter, Julie A; Abrahams, Vikki M (2013) Human endometrial endothelial cells generate distinct inflammatory and antiviral responses to the TLR3 agonist, Poly(I:C) and the TLR8 agonist, viral ssRNA. Am J Reprod Immunol 70:190-8

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