NF-κB regulation in maternal immunity during normal and IUGR pregnancies

Abstract

Intrauterine Growth Restriction (IUGR) is a leading cause of perinatal death with no effective cure, affecting 5–10% pregnancies globally. Suppressed pro-inflammatory Th1/Th17 immunity is necessary for pregnancy success. However, in IUGR, the inflammatory response is enhanced and there is a limited understanding of the mechanisms that lead to this abnormality. Regulation of maternal T-cells during pregnancy is driven by Nuclear Factor Kappa B p65 (NF-κB p65), and we have previously shown that p65 degradation in maternal T-cells is induced by Fas activation. Placental exosomes expressing Fas ligand (FasL) have an immunomodulatory function during pregnancy. The aim of this study is to investigate the mechanism and source of NF-κB regulation required for successful pregnancy, and whether this is abrogated in IUGR. Using flow cytometry, we demonstrate that p65+ Th1/Th17 cells are reduced during normal pregnancy, but not during IUGR, and this phenotype is enforced when non-pregnant T-cells are cultured with normal maternal plasma. We also show that isolated exosomes from IUGR plasma have decreased FasL expression and are reduced in number compared to exosomes from normal pregnancies. In this study, we highlight a potential role for FasL+ exosomes to regulate NF-κB p65 in T-cells during pregnancy, and provide the first evidence that decreased exosome production may contribute to the dysregulation of p65 and inflammation underlying IUGR pathogenesis.

Extracellular vesicles and immune response during pregnancy: A balancing act*

“…Data regarding immune‐mediated mechanisms and the role of EVs in pregnancies complicated by fetal growth restriction without preeclampsia are scant. Isolated sEVs from the plasma of women with fetal growth restriction exhibit reduced levels of sEVs that carry Fas‐L, leading to less T cell suppression, as observed in normal pregnancy 229 . In women with fetal growth restriction, we found no change in the number or size of maternal plasma sEVs or their miRNA cargo 217 …”

“…Isolated sEVs from the plasma of women with fetal growth restriction exhibit reduced levels of sEVs that carry Fas-L, leading to less T cell suppression, as observed in normal pregnancy. 229 In women with fetal growth restriction, we found no change in the number or size of maternal plasma sEVs or their miRNA cargo. 217…”

The exosome: a review of current therapeutic roles and capabilities in human reproduction

“…3 The morphology of a placental exosomes, noting the roles of specific markers which mainly relate to immunomodulatory functions [36,47], together with cellular signalling and recognition markers [47], which include placenta-specific domains [35] involved in reproductive processes [43]. The downregulation of the T cell immune response assists with appropriate foetal recognition and by extension regulates inflammatory pathways [51].…”

“…For example, previous research has shown that an increase in a Th1 immune response and cytokines (TNF-α, CXCL10, and IFN-γ) has been associated with pro-inflammatory pathways and an increased incidence of adverse developmental events and miscarriages [52,53]. Hence, exosomes which carry syncytin-1 may reduce the occurrence of adverse maternal events and assist in regulating the levels of inflammation during the multiple stages of conception [50][51][52][53].…”

Extracellular vesicles in reproduction and pregnancy

“…Alter metabolic pathways associated with GDM [172] Mediate glucose intolerance during pregnancy [173] Gestational diabetes mellitus N/A Insulin secretion and regulation; Glucose transport [173,174] Placenta Biomarkers of placental function [175] Increase inflammation in maternal uterine cells [176] Amnion epithelial cells Carry HMGB1; Induce labor [177] Group B Streptococcus Induce labor [178] Preterm birth N/A Biomarkers of preterm labor [179][180][181] Placenta Mediate maternal immune tolerance to the fetus [140,182 ] Fetal growth restriction Umbilical cord blood Reduce angiogenic properties of human umbilical vein endothelial cells [183] EVs: Extracellular vesicles; GDM: gestational diabetes mellitus. circulation [161] .…”