Increasing interests are focused on immune-modulation during pregnancy. Amniotic fluid (AF) is a complex and dynamic environment essential for fetal evelopment and maturation. AF is a rich source of extracellular vesicles (EVs), membrane enclosed spherical particles, deeply involved in cell-cell communication and in a wide range of biological responses, including immune-modulation. Despite the growing interest on EVs, AF-derived EVs (AF-EVs) role remains largely under-investigated. Here, we demonstrated, for the first time, that AFEVs induce a significant reduction in THP-1 monocyte cell viability. This effect is accompanied by pyroapototic-morphological changes, suggesting an immune-modulatory role for AF-EVs. At the molecular level AF-EVs exposure induced an increase in Absent in Melanoma 2 (AIM2) expression and Caspase-1 activation, without affecting Nucleotide oligomerization domainlike receptors 1 (NLRP1) and 3 (NLRP3) protein expression. These effects are paralleled by pro-IL1beta up-regulation. FACS analysis demonstrated that AF-EVs are not internalized by THP-1 cells, thus excluding EVs cargo-dependent activity inside recipient cells. We hypothesized that the observed effects may be ascribed to extracellular adenosine production by AF-EVs. Indeed: (i) AF-EVs are capable of producing ATP, (ii) AF-EVs possess all the enzymes necessary to convert the nucleotide triphosphate into adenosine, i.e. CD39 (ecto-nucleoside triphosphate diphosphohydrolase 1) and CD73 (ecto-5’nucleotidase) and (iii) THP-1 cells express adenosine receptors. In agreement, adenosine receptor agonist NECA mirrors whereas adenosine receptor antagonist Caffeine reverts AF-EVs-induced Caspase-1 activation. All together these results suggest that, by inducing monocyte pyroapoptotic cell death, AF-EVs exert a immune-regulatory function. These data unveil a novel role for AF-EVs in the immune response at the maternal-fetal interface that can contribute to semi-allogenic fetus protection.

AMNIOTIC FLUID EXTRACELLULAR VESICLES: NOVEL PLAYER IN THE IMMUNEMODULATION DURING PREGNANCY

Letizia Mezzasoma;Ilaria Bellezza;Marco Gargaro;Giorgia Manni;Rita Romani;Vincenzo Nicola Talesa
2019

Abstract

Increasing interests are focused on immune-modulation during pregnancy. Amniotic fluid (AF) is a complex and dynamic environment essential for fetal evelopment and maturation. AF is a rich source of extracellular vesicles (EVs), membrane enclosed spherical particles, deeply involved in cell-cell communication and in a wide range of biological responses, including immune-modulation. Despite the growing interest on EVs, AF-derived EVs (AF-EVs) role remains largely under-investigated. Here, we demonstrated, for the first time, that AFEVs induce a significant reduction in THP-1 monocyte cell viability. This effect is accompanied by pyroapototic-morphological changes, suggesting an immune-modulatory role for AF-EVs. At the molecular level AF-EVs exposure induced an increase in Absent in Melanoma 2 (AIM2) expression and Caspase-1 activation, without affecting Nucleotide oligomerization domainlike receptors 1 (NLRP1) and 3 (NLRP3) protein expression. These effects are paralleled by pro-IL1beta up-regulation. FACS analysis demonstrated that AF-EVs are not internalized by THP-1 cells, thus excluding EVs cargo-dependent activity inside recipient cells. We hypothesized that the observed effects may be ascribed to extracellular adenosine production by AF-EVs. Indeed: (i) AF-EVs are capable of producing ATP, (ii) AF-EVs possess all the enzymes necessary to convert the nucleotide triphosphate into adenosine, i.e. CD39 (ecto-nucleoside triphosphate diphosphohydrolase 1) and CD73 (ecto-5’nucleotidase) and (iii) THP-1 cells express adenosine receptors. In agreement, adenosine receptor agonist NECA mirrors whereas adenosine receptor antagonist Caffeine reverts AF-EVs-induced Caspase-1 activation. All together these results suggest that, by inducing monocyte pyroapoptotic cell death, AF-EVs exert a immune-regulatory function. These data unveil a novel role for AF-EVs in the immune response at the maternal-fetal interface that can contribute to semi-allogenic fetus protection.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/1463285
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