Role of Toll-Like Receptors and Glucocorticoid in Placental-Fetal Inflammation
A 2003 report by the American Academy of Pediatricians and the American College of Obstetricians and Gynecologists concluded that most cases of newborn encephalopathy and cerebral palsy (CP) were not due to acute processes originating during labor, but instead were attributable to perinatal events such as infection and coagulation disorders. Although specific etiologies of CP remain unknown, recent studies show a strong correlation between fetal/placental inflammation, microbial infection of the placenta, and poor neonatal outcome. Innate cellular immune responses are initiated by the interaction of microbial pathogens with Toll-like receptors (TLRs). TLR-2 and -4 recognize compounds present in bacteria, whereas viral products signal through TLR-3. Binding of ligand to TLR activates NF-κB, a transcription factor that stimulates the expression of cytokines and other mediators of inflammation. NF-κB 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.
The studies of Project III provide insight into the pathogenesis of CP by trying to elucidate the mechanisms through which microbes trigger inflammatory pathways in human placenta. These studies work under the hypothesis that:
- GC action modulates TLR-dependent cytokine and chemokine expression in syncytiotrophoblasts (SCTs), fibroblasts (FIBs), and fetal macrophages (i.e. Hofbauer cells, HBCs) to protect the fetus against microbial compounds as well as limiting inflammation at this site
- TLR-dependent inflammatory pathways dominate in pregnancies complicated by fetal/placental infections and promote neurological impairment in infants
Aim I. To determine the mechanism(s) through which GC action suppresses TLR-2, -3, and -4 signaling in placenta if TLR-driven processes in placenta
Preliminary results suggest that GC treatment suppresses TLR-4 function through pathways involving interaction of NFkB and both IkBalpha and IkBbeta (inhibitors of the NFkB pathway)
Aim II. To determine if TLR-driven processes in placenta provide novel signatures of fetal/placental inflammation leading to impaired neurological development in infants
Preliminary results suggest that the presence of microbial products enhances monocyte chemotactic protein-1 expression in SCTs and FIBs which promotes increased infiltration of fetal macrophages (i.e. Hofbauer cells, HBCs) to the placental villus in pregnancies complicated by chorioamniontis (CA) and funitis
Aim III. To determine if maternal administration of GC suppresses LPS-driven fetal/placental inflammation and neonatal brain injury in mice following intrauterine infusion of LPS on gestational day 15
These studies will provide insight into microbial-driven, cell type-specific inflammatory pathways in human placenta and how they impact fetal well-being
Toti P, Arcuri F, Tand, Z, Schatz F, Zambrano E, Mor G, Niven-Fairchild T, Abrahams VM, Krikun G, Lockwood CJ, Guller S. Focal increase of fetal macrophages in placentas from pregnancies with histological choroamnionitis; potential role of fibroblast monocyte chemotactic protein-1. Am J Reprod Immunol 2011; 65:470-479.
Tang Z, Tadesse S, Norwitz E, Mor G, Abrahams VM, Guller S. Isolation of Hofbauer cells from human term placentas with high yield and purity. Am J Reprod Immunol 2011; 66:336-348.
Mor G, Cardenas I, Abrahams VM, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. In:Reprod Science (Seth Guller, Carlo Bulletti, Dominique de Zeigler, eds). Ann NY Acad Sci 2011; 1221:80-87
Tang Z, Abrahams VM, Mor G, Guller S. Placental Hofbauer cells and complications of pregnancy. In: Reprod Science (Seth Guller, Carlo Bulletti, Dominique de Zeigler, eds). Ann Ny Acad Sci 2011; 1221:103-108