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

Abstract

Successful embryo implantation occurs followed by a local inflammatory/Th1 response, subsequently redirected towards a tolerogenic predominant profile. The lack of a control of this initial local inflammatory response may be an underlying cause of early pregnancy complications as recurrent spontaneous abortions (RSA). Considering that VIP mediates anti-inflammatory and tolerogenic effects in several conditions we hypothesized that VIP may contribute to the tolerance towards trophoblast antigens during the early interaction of maternal leukocytes and trophoblast cells. Here we investigated VIP/VPAC system activity and expression on maternal PBMCs after the interaction with immortalized trophoblast cells (Swan-71 cell line) as an in vitro model of feto-maternal interaction and we analyzed whether it modulates maternal Treg/Th1 responses. We also investigated the contribution of endogenous VIP/VPAC system to RSA pathogenesis. VIP significantly decreased T-bet expression, reduced MCP-1 and nitrite production in co-cultures of fertile women PBMCs with trophoblast cells; while it increased the frequency of CD4+CD25+Foxp3+ cells, TFG expression and IL-10 secretion. These effects were prevented by VIP specific antagonist. Interestingly, PBMCs from RSA patients displayed significantly higher T-bet expression, lower Treg frequency and lower frequency of VIP-producer CD4 lymphocytes after the interaction with trophoblast cells. Moreover, the patients displayed significantly lower frequency of endometrial CD4+VIP+ cells in comparison with fertile women. Conclusion: VIP showed a Th1-limiting and Treg-promoting response in vitro that would favor early pregnancy outcome. Since RSA patients displayed defects in the VIP/VPAC system, this neuropeptide could arise as a promising candidate for diagnostic biomarker or surrogate biomarker for recurrent spontaneous abortions.