VIP boosts regulatory T cell induction by trophoblast cells in an in vitro model of trophoblast–maternal leukocyte interaction

Fraccaroli, Laura Virginia; Grasso, Esteban; Hauk, Vanesa; Paparini, Daniel; Soczewski, Elizabeth; Mor, Gil; Leirós, Claudia Pérez; Ramhorst, Rosanna

doi:10.1189/jlb.1a1014-492rr

Cited by 23 publications

(41 citation statements)

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“…VIP is expressed in the human uterus (29), and VIP plasma levels are increased in pregnant vs. nonpregnant women (30). Human first-and thirdtrimester placentas and different human trophoblast cell lines express VIP (31)(32)(33). Moreover, VIP increases progesterone and human chorionic gonadotrophin secretion in human trophoblast cells (31), activates trophoblast migration and invasion through VIP receptor type 1 and 2, and regulates the interaction of trophoblast cells with maternal leukocytes through autocrine and paracrine loops (32,34).…”

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confidence: 99%

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

et al. 2018

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Immune homeostasis maintenance throughout pregnancy is critical for normal fetal development. Trophoblast cells differentiate into an invasive phenotype and contribute to the transformation of maternal arteries and the functional shaping of decidual leukocyte populations. Insufficient trophoblast invasion, inadequate vascular remodeling, and a loss of immunologic homeostasis are associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction. Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide synthetized in trophoblasts at the maternal-placental interface. It regulates the function of trophoblast cells and their interaction with decidual leukocytes. By means of a murine model of pregnancy in normal maternal background with VIP-deficient trophoblast cells, here we demonstrate that trophoblast VIP is critical for trophoblast function: VIP gene haploinsufficiency results in lower matrix metalloproteinase 9 expression, and reduced migration and invasion capacities. A reduced number of regulatory T cells at the implantation sites along with a lower expression of proangiogenic and antiinflammatory markers were also observed. Findings detected in the implantation sites at early stages were followed by an abnormal placental structure and lower fetal weight. This effect was overcome by VIP treatment of the early pregnant mice. Our results support the relevance of trophoblast-synthesized VIP as a critical factor in vivo for trophoblast-cell function and immune homeostasis maintenance in mouse pregnancy.-Hauk, V., Vota, D., Gallino, L., Calo, G., Paparini, D., Merech, F., Ochoa, F., Zotta, E., Ramhorst, R., Waschek, J., Leirós, C. P. Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice.

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Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

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“…Likewise, dose‐dependent stimulation of progesterone release by VIP was reported in JEG‐3 cells and human trophoblast primary cultures . VIP and VPAC receptors are also expressed in the human first trimester trophoblast cell line Swan 71 . In this cell line, and in the HTR8/SVNeo human cytotrophoblast cell line, VIP promoted trophoblast cell migration and invasion through CRE–PKA pathways .…”

Section: Vip: An Emerging Candidate As a Pregnancy Regulatory Neuropementioning

confidence: 71%

“…Neutrophils are deactivated and driven to apoptosis thus also enhancing their clearance through immunosuppressive phagocytosis. In line with these responses, VIP mediated TGF‐β induction of regulatory T lymphocytes in a trophoblast‐dependent manner . This novel immunomodulatory role of trophoblast VIP on maternal leukocytes might provide new clues for pharmacological targeting of immune and trophoblast cells in pregnancy complications associated with exacerbated inflammation.…”

Section: Regulatory Loops Involving Vip At the Trophoblast–immune Intmentioning

confidence: 75%

“…VIP induced chemokine synthesis in Swan 71 cells, particularly monocyte, neutrophil, and T lymphocyte chemoattractant molecules such as CXCL8, CCL5 (RANTES), CCL2 (MCP‐1), and CCL3 (MIP‐1α) . VIP added to cocultures of human trophoblast Swan 71 cells and human peripheral blood mononuclear cells (PBMCs) was shown to boost an immunosuppressive and tolerogenic response by T lymphocytes in vitro through TGF‐β–mediated pathways . On the other hand, VIP priming of the trophoblast cell lines Swan 71 and HTR8/SVNeo modulated monocyte and macrophage phenotypes favoring a predominant anti‐inflammatory and M2 alternative activation profile, respectively .…”

Section: Regulatory Loops Involving Vip At the Trophoblast–immune Intmentioning

confidence: 99%

“…CyRE, gp130 family cytokine response element; CRE, cAMP response element; Gs, stimulatory G protein; AC, adenylate cyclase; LIF, leukemia inhibitory factor; LIFR/gp130, heterodimer complex composed of the LIF receptor subunit and the gp130 subunit. The figure illustrates trophoblast–immune interactions and the effects of VIP as derived from previous reports …”

Section: Regulatory Loops Involving Vip At the Trophoblast–immune Intmentioning

confidence: 99%

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Control of the inflammatory response during pregnancy: potential role of VIP as a regulatory peptide

Ramhorst

Calo

Paparini

et al. 2018

Annals of the New York Academy of Sciences

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A network of cell-cell communications through contact and soluble factors supports the maternal-placental interaction and provides a suitable environment for fetal growth. Trophoblast cells take center stage at these loops: they interact with maternal leukocytes to sustain the varying demands of gestation, and they synthesize hormones, cytokines among other factors that contribute to the maintenance of immune homeostasis. Here, we discuss vasoactive intestinal peptide (VIP) and its potential as a regulatory neuropeptide in pregnancy. VIP is synthesized by trophoblast cells; it regulates trophoblast cell function and interaction with the major immune cell populations present in the pregnant uterus. VIP activity produces an anti-inflammatory microenvironment by modulating the functional profile of monocytes, macrophages, and regulatory T cells. Trophoblast VIP inhibits neutrophil extracellular trap formation and accelerates neutrophil apoptosis, enabling their silent clearance by phagocytic cells. The effects of VIP on the trophoblast-immune interaction are consistent with its regulatory role throughout pregnancy for immune homeostasis maintenance. These observations may provide new clues for pharmacological targeting of pregnancy complications associated with exacerbated inflammation.

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Interplay between neutrophils and trophoblast cells conditions trophoblast function and triggers vascular transformation signals

Calo

Sabbione

Pascuali

et al. 2019

Journal Cellular Physiology

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Normal placentation entails highly regulated interactions of maternal leukocytes with vascular and trophoblast cells to favor vascular transformation. Neutrophil activation and neutrophil extracellular trap (NET) formation associate with poor placentation and severe pregnancy complications. To deepen into the mechanisms of trophoblast–neutrophil interaction, we explored the effects of NETs on trophoblast cell function and, conversely, whether trophoblast cell‐derived factors condition neutrophils to favor angiogenesis and anti‐inflammatory signals required for fetal growth. NETs isolated from activated neutrophils hindered trophoblast cell migration. Trophoblast conditioned media prevented the effect as well as the vasoactive intestinal peptide (VIP) known to regulate trophoblast and neutrophil function. On the other hand, factors released by trophoblast cells and VIP shaped neutrophils to a proangiogenic profile with increased vascular endothelial growth factor synthesis and increased capacity to promote vascular transformation. Results presented here provide novel clues to reconstruct the interaction of trophoblast cells and neutrophils in vivo during placentation in humans.

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VIP boosts regulatory T cell induction by trophoblast cells in an in vitro model of trophoblast–maternal leukocyte interaction

Cited by 23 publications

References 55 publications

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

Control of the inflammatory response during pregnancy: potential role of VIP as a regulatory peptide

Interplay between neutrophils and trophoblast cells conditions trophoblast function and triggers vascular transformation signals

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