VIP-DEFICIENCY IN TROPHOBLAST CELLS UNDERLIES IMMUNE HOMEOSTASIS LOSS AT THE MATERNAL-PLACENTAL INTERFACE

HAUK, VANESA; VOTA, DAIANA; GALLINO, LUCILA; PAPARINI, DANIEL; CALO, GUILLERMINA; MERECH, FÁTIMA; WASCHEK, JAMES; RAMHORST, ROSANNA; PÉREZ LEIRÓS, CLAUDIA

Roma

Congreso; X ISNIM Congress; 2017

International Society of Neuroimmunomodulation

Trophoblast cells modulate leukocyte recruitment and immune shaping to a predominant anti-inflammatory profile for proper placentation and fetal growth. Placentation is associated withtrophoblast cell differentiation into invasive phenotypes, activation of matrix metalloproteinases(MMP) as well as trophoblast-immune cell interaction to maintain immune homeostasis.Vasoactive intestinal peptide (VIP) is a 28 amino acid pleiotropic neuropeptide with vasodilating,pro-secretory and anti-inflammatory effects through binding high affinity VPAC1 and VPAC2 receptors. We hypothesized that VIP synthesized by trophoblast cells regulate trophoblast cell function and their interaction with immune cells thus contributing to fetal growth and successful pregnancy.We studied pregnancy outcome associated to trophoblast and immune cell phenotype and functional markers in VIP deficient mice. Trophoblast giant cells (TGC) were isolated from implantation sites of C57BL/6 WT females mated to VIP-/- or WT males at day 7,5-8,5 by laser capture microdissection for the analysis of TGC markers, VPAC expression and MMP9 by RTqPCR. Ectoplacental cones were cultured for trophoblast cell functional studies. Immune marker expression was determined by RTqPCR and Treg cell recruitment to the implantation sites was assessed in VIP WT GFP+ females crossed with VIP -/- males by flow cytometry.VIP deficient pregnancies showed reduced litter size, increased period inter-gestations and asymmetric distribution of implantation sites in the uterus. IL-10 decreased expression and a lower percentage of Foxp3-GFP+ Treg cells within CD4+ cells in implantation sites of WT mothers crossed with VIP -/- males compared with WTxWT were observed. VIP-deficient trophoblast cells showed lower outgrowth migration and three-fold decreased expression of MMP9, a marker of trophoblast invasiveness, whereas a VIP antagonist reduced trophoblast invasiveness on Matrigel in VIP WT females.These results support the relevance of trophoblast VIP in autocrine and paracrine loops to maintain trophoblast cell function and an immunosuppressant microenvironment at the maternal-placental interface.