Potential immunomodulatory role of VIP in the implantation sites of prediabetic nonobese diabetic mice

Abstract

Among several factors known to modulate embryo implantation and survival, uterine quiescence and neovascularization, maternal immunotolerance through the Th1/Th2 cytokine balance towards a Th2 profile, local regulatory T-cell (Treg) activation, and high levels of progesterone were assigned a prominent role. Vasoactive intestinal peptide (VIP) is a neuroimmunopeptide that has anti-inflammatory effects, promotes Th2 cytokines and CD4C Treg activation, and stimulates exocrine secretion, smooth muscle relaxation, and vasodilatation favoring uterus quiescence. The goal of the present work was to explore the participation of VIP in the implantation sites of normal and pregnant prediabetic nonobese diabetic (NOD) females, a mouse strain that spontaneously develops an autoimmune exocrinopathy similar to Sjö gren's syndrome. Our results indicate a reduction in litter size from the third parturition onwards in the NOD female lifespan with increased resorption rates. Progesterone systemic levels were significantly decreased in pregnant NOD mice compared with BALB/c mice, although the allogeneic response to progesterone by spleen cells was not impaired. VIP receptors, Vipr1 and Vipr2 (Vpac1 and Vpac2), were expressed at the implantation sites and VIP induced leukemia inhibitory factor (LIF) and Treg marker expression in both strains; however, a reduced Vip expression was found in NOD implantation sites. We conclude that the reduced birth rate at 16-week-old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of VIP at the sites of implantation, which acts as a local inducer of pro-implantatory LIF and Treg activation.

Defects in the vasoactive intestinal peptide (VIP)/VPAC system during early stages of the placental–maternal leucocyte interaction impair the maternal tolerogenic response

“…To our knowledge, this is the first report showing that deficiencies in VIP production could be associated with recurrent pregnancy loss. In line with this, in NOD mice, which show pregnancy complications and an increased rate of embryo resorption at the prediabetic stage, the local expression of VIP mRNA was diminished at viable implantation sites compared with control mice .…”

“…In the feto-maternal context, we have shown recently that VIP is present in viable implantation sites of normal mice, where it induces Treg cells [20]. In line with this, lower levels of VIP and forkhead box protein P3 (FoxP3) were found in viable implantation sites of prediabetic non-obese diabetic (NOD) mice, characterized by a Th1 systemic cytokine profile, correlating with a reduction in litter size from 16 weeks of age and increased resorption rates [20]. Interestingly, functional VIP receptors VPAC1 and VPAC2 were expressed at the implantation sites from pregnant BALBc and NOD mice, and a significant increase of FoxP3 expression was induced by VIP in both strains.…”

Adaptive Immune Responses During Pregnancy

“…66 This is further confirmed in VIP À/À fetuses that highlights the role of maternal VIP for early neural development. 67 Current data position VIP as an important immunomodulatory molecule as it can increase the frequency of Treg and LIF at implantation sites in mice 68 and supports a tolerogenic macrophage phenotype. 64 It seems that both hormones and polypeptides are involved in the recruitment of immune cells into the fetal-maternal interface and in the generation of a tolerogenic immune response toward the fetus.…”

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

“…Pregnant uteri were carefully dissected at d 8.5 of pregnancy, and implantation sites were defined as previously described (42,50) and isolated for cytokine and transcription factors measurement by RT-PCR, or preserved in paraformaldehyde 4% for histologic features or in optimal cutting temperature compound (Biopack, Buenos Aires, Argentina) for laser capture microdissection (LCM). For the preparation of EPC explants, the embryos at gestational d 8.5 were dissected from the implantation sites, and then the EPC was separated from each embryo using sterile fine forceps (51).…”