Abstract
During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle-mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus.We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus.
Highlights
Exosomes are small 30–150 nm vesicles formed within cells by inward budding of the limiting membrane of multivesicular bodies (MVBs) within the cytoplasm
Whilst the release of extracellular vesicles from the placenta is a normal process of pregnancy, elevated production of placental microvesicles and exosomes, and their heightened pro-inflammatory effect on maternal immune cells are both implicated in pre-eclampsia, a disorder of pregnancy characterized by systemic inflammation [7,14]
Uptake of macrophage exosomes by human trophoblast cells To determine if placental trophoblast cells take up immune cell exosomes, we initially investigated macrophage exosome uptake kinetics in the BeWo cell line
Summary
Exosomes are small 30–150 nm vesicles formed within cells by inward budding of the limiting membrane of multivesicular bodies (MVBs) within the cytoplasm. Whilst the release of extracellular vesicles from the placenta is a normal process of pregnancy, elevated production of placental microvesicles and exosomes, and their heightened pro-inflammatory effect on maternal immune cells are both implicated in pre-eclampsia, a disorder of pregnancy characterized by systemic inflammation [7,14]. Whilst it is widely accepted that placenta-derived extracellular vesicles can influence the maternal immune response during pregnancy, bi-directional trafficking between immune cells and the placenta has yet to be explored This is important because the placenta mounts its own immunological responses to infection: TLRs, which recognize and respond to pathogen-associated-molecular-patterns (PAMPs), are present in the human placenta throughout gestation [15,16], and stimulation of these placental TLRs results in a robust cytokine response by trophoblast cells [11,17]. The human placenta is an active immunological organ, which can respond both to infectious agents and to activation signals from the maternal immune system
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