VIP in vivo treatment modulates maternal macrophage activation profile and efferocytic ability in the CBAxDBA resorption prone model
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1
CONICET, IQUIBICEN, University of Buenos Aires, Argentina
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2
Institute of Experimental Medicine IMEX-CONICET, National Academy of Sciences, Argentina
Homeostasis maintenance at the feto-maternal interface is the result of multiple processes that occur at local and systemic levels which require several ongoing signals and checkpoints. Immune cells involved in the control of the early inflammatory response have a central role at the maternal-placental interface such as the activation of macrophages in an alternative profile. Particularly VIP, vasoactive intestinal peptide, mediates immune and nervous effector functions and has emerged as a potential effective treatment for inflammatory and autoimmune disorders based on its anti-inflammatory and tolerogenic effects as it was demonstrated in mouse models of inflammation through its action on macrophages and T cell VPAC receptors. Since the control of the initial inflammatory response after embryo implantation appears to be crucial for a successful outcome and considering that VIP mediates anti-inflammatory and tolerogenic immune effects, we hypothesized that VIP participates in homeostasis maintenance at the early maternal-placental interface inducing an immunosuppresant microenvironment through efferocytosis associated with an alternative activation profile of maternal macrophages.
We used the mating of CBA/J females (H2k) with DBA/2 males (H2d) that provokes spontaneously high resorption rates associated with a failure in the maternal tolerogenic response and we investigated whether in vivo VIP treatment contributes to an immunosuppressant local microenvironment associated with an improved pregnancy outcome.
Thereore, implantation sites from the CBA/J × DBA/2 mating females on day 8.5 of gestation were isolated after in vivo VIP treatment (2nmol/mouse i.p.) or PBS on day 6.5. for VIP/VPAC, Foxp3, RORγt, TGF-beta and PPAR gamma expression was assessed by RT-PCR. Peritoneal macrophages were obtained at day 8.5 and efferocytic ability was tested using latex beads-FITC or apoptotic thymocytes, evaluated by FACS and microscopy respectively. Supernatants were obtained and TNF-alfa and IL-12 tested by ELISA while IL-10 by FACS analysis.
We could oberve that pregnancy induced the expression of VIP, VPAC1 and VPAC2 in the uterus compared with non-pregnant mice. VIP treatment significantly increased the number of viable implantation sites and improved the asymmetric distribution of implanted embryos. This effect was acompained by a decrease in RORγt and increase in TGF-beta and PPAR-gamma expression at the implantation sites. On the other hand, VIP modulated the efferocytosis evaluated by two complementary approaches, the efferocytosis of latex beads and of apoptotic thymocytes. In addition, VIP treatment in vivo increased the frequency of F4/80 cells IL-10-producers while did not modulate TNF-alfa and IL-12 secretion suggesting their activation in an alternative profile.
The present results provide new data that the in vivo treatment with VIP prevents embryo resorption and improves pregnancy end points evidenced as an increase in the number of viable embryo with a symmetric distribution in the uterine horns associated with an increase in the efferocytic ability of maternal macrophages associated with an immunosuppressant microenvironment.
Acknowledgements
This study was supported by grants to CPL and RR from: CONICET (PIP 2659), University of Buenos Aires (UBAcyt 2011-2014 and 2012-2015) and from ANPCyT (PICT 2011-0144, 2013-1632).
Keywords:
Vasoactive Intestinal Peptide,
Maternal Tolerance,
Efferocytosis,
Macrophage Activation,
CBA mice
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Poster Presentation
Topic:
Immunology of reproduction
Citation:
Gallino
L,
Calo
G,
Hauk
V,
Fraccaroli
L,
Grasso
E,
Vermeulen
M,
Perez Leiros
C and
Ramhorst
R
(2015). VIP in vivo treatment modulates maternal macrophage activation profile and efferocytic ability in the CBAxDBA resorption prone model.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00103
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Received:
26 May 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
PhD. Rosanna Ramhorst, CONICET, IQUIBICEN, University of Buenos Aires, Buenos Aires, Buenos Aires, C1428EHA, Argentina, rramhorst@qb.fcen.uba.ar