Role of Toll-Like Receptors and Glucocorticoid in Placental/Fetal Inflammation

Yale University, New Haven CT

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Abstract

It has recently been concluded that most cases of cerebral palsy (CP) are attributable to perinatal events such as infection and coagulation disorders that activate inflammatory pathways in the fetus and placenta. In this application we propose experiments to elucidate the mechanisms through which microbes trigger inflammatory pathways in the human term placenta. Innate cellular immune responses are mediated by the interaction of pathogens with Toll-like receptors (TLRs). Binding of ligand to TLR activates NF-KB, a transcription factor that stimulates the expression of cytokines and other mediators of inflammation. NF-KB function is suppressed by glucocorticoid (GC) through glucocorticoid receptor (GR) action, although the interaction of TLR and GR pathways in human placenta remains largely unexplored. Our working hypothesis is that GC action modulates TLR-dependent cytokine expression in placental syncytiotrophoblasts (SCTs) and fibroblasts (FIBs) to achieve a dual purpose;protection of the fetus against microbial compounds while limiting inflammation at this site. Furthermore, we postulate that TLR-dependent pathways dominate in pregnancies complicated by fetal/placental inflammation and promote neurological impairment in infants. In our three specific aims we will: 1) determine the mechanism(s) through which GC action suppresses TLR-2,- 3, and -4-mediated cytokine expression in placenta;2) test the hypothesis that SCTs and FIBs, in a TLRdriven process, promote inflammation and recruit monocytes and macrophages to the placental villus in pregnancies associated with chorioamnionitis and neurodevelopmental delay in infants;and 3) test the hypothesis that maternal administration of GC suppresses TLR-4-driven fetal/placental inflammation and neonatal brain injury in mice following intrauterine infusion of LPS on gestational day 15.. For studies we will couple physiologically relevant in vitro techniques of primary cell culture, dual (maternal + fetal) placental perfusion, and mouse knockout models with state of the art molecular methodologies including laser capture microdissection (LCMD) and real-time quantitative PCR (qRTPCR).