Project I.

Role of Toll-like receptors in trophoblast immune regulation

Toll-like Receptors (TLRs) mediate trophoblast recognition of the uterine microenvironment that under normal conditions contain commensal microbes and stress proteins, and respond to it by recruiting a large number of immune cells, such as macrophages, Natural killer (NK) cells and regulatory T cells (Treg), all found in the decidua. The appropriate communication between all these cellular components at the maternal-fetal interface is crucial for successful reproduction. TLRs expressed by the trophoblast function as sensors which induce the production of cytokines/chemokines that will in turn regulate immune cell distribution and function at the maternal-fetal interface. However, if the function of TLRs is left unchecked, the maternal-fetal interface may become overwhelmed by immune activation. Therefore, TLR function and signaling must be tightly regulated in order to prevent pathological conditions.

The studies of Project I evaluate the supportive regulatory interactions between first trimester trophoblasts and the maternal immune system. They also investigate the role of Toll-like Receptors (TLR) in these processes. The objectives of Project I are to:

  • Understand TLR function in first trimester trophoblast cells
  • Determine the effects of trophoblast TLR activation on maternal immune cells
  • Characterize regulatory mechanisms controlling TLR expression and function at the maternal-fetal interface
  • Evaluate the role of TLRs in pregnancy outcome 

Aim I: Determine cytokine profile in first trimester trophoblast cells following TLR ligation  

As trophoblast express TLR's on their cell surface, they are able to recognize and respond to endogenous lignads present in the microenvironment. This aim elucidates the effect of endogenous ligands on TLR-4 induced cytokine response and survival in trophoblast cells, TLR-mediated production of antimicrobial factors by trophoblast cells and the role of estrogen on the regulation of TLR expression and function 

Aim II: Characterize the effect of trophoblast TLR activation on immune cell recruitment and function

Differentiation and function of immune cells infiltrating the implantation site depends, largely in part, on the microenvironment created by the placenta. Trophoblast cells can induce the differentiation of immune cells into trophoblast-supporting phenotype. This aim will determine what is the phenotype and function of monocytes differentiated by trophoblast cells as well as the effect of trophoblast cells on T-cell differentiation and activation 

Aim III: Study the regulation of TLR expression and function in trophoblast cells

Excessive activation or dampened responses of TLRs may lead top pathological conditions. Therefore, TLR signaling in trophoblast cells must be under tight regulation.  Aim III focuses on the role of IKKb in the regulation of trophoblast responses to stimulation by TLR-4 or TLR-3 ligands and the role of cytokines on the function of intracellular regulators of the TLR-3 and TLR-4 pathways 

Aim IV: In vivo studies for the characerization of TLR function in pregnancy. 

TLRs expressed on trophoblast coordinate the maternal immune response towards pathogens and an abnormal immune response may lead to pregnancy failure. In order to dissect the role of fetal vs. maternal TLR during implantation and pregnancy, we use embryo transfer of wild-type and TLR-deficient mice to determine the role of both maternal and fetal TLR responses 

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