VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment
Uterine receptivity and embryo implantation are two main processes that need a finely regulated balance between pro-inflammatory and tolerogenic mediators to allow a successful pregnancy. The neuroimmune peptide vasoactive intestinal peptide (VIP) is a key regulator, and it is involved in the induct...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02907/full |
| _version_ | 1819161929710567424 |
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| author | Lucila Gallino Vanesa Hauk Laura Fernández Elizabeth Soczewski Soledad Gori Esteban Grasso Guillermina Calo Nora Saraco Esperanza Berensztein James A. Waschek Claudia Pérez Leirós Rosanna Ramhorst |
| author_facet | Lucila Gallino Vanesa Hauk Laura Fernández Elizabeth Soczewski Soledad Gori Esteban Grasso Guillermina Calo Nora Saraco Esperanza Berensztein James A. Waschek Claudia Pérez Leirós Rosanna Ramhorst |
| author_sort | Lucila Gallino |
| collection | DOAJ |
| description | Uterine receptivity and embryo implantation are two main processes that need a finely regulated balance between pro-inflammatory and tolerogenic mediators to allow a successful pregnancy. The neuroimmune peptide vasoactive intestinal peptide (VIP) is a key regulator, and it is involved in the induction of regulatory T cells (Tregs), which are crucial in both processes. Here, we analyzed the ability of endogenous and exogenous VIP to sustain a tolerogenic microenvironment during the peri-implantation period, particularly focusing on Treg recruitment. Wild-type (WT) and VIP-deficient mice [heterozygous (HT, +/−), knockout (KO, −/−)], and FOXP3-knock-in-GFP mice either pregnant or in estrus were used. During the day of estrus, we found significant histological differences between the uterus of WT mice vs. VIP-deficient mice, with the latter exhibiting undetectable levels of FOXP3 expression, decreased expression of interleukin (IL)-10, and vascular endothelial growth factor (VEGF)c, and increased gene expression of the Th17 proinflammatory transcription factor RORγt. To study the implantation window, we mated WT and VIP (+/−) females with WT males and observed altered FOXP3, VEGFc, IL-10, and transforming growth factor (TGF)β gene expression at the implantation sites at day 5.5 (d5.5), demonstrating a more inflammatory environment in VIP (+/−) vs. VIP (+/+) females. A similar molecular profile was observed at implantation sites of WT × WT mice treated with VIP antagonist at d3.5. We then examined the ability GFP-sorted CD4+ cells from FOXP3-GFP females to migrate toward conditioned media (CM) obtained from d5.5 implantation sites cultured in the absence/presence of VIP or VIP antagonist. VIP treatment increased CD4+FOXP3+ and decreased CD4+ total cell migration towards implantation sites, and VIP antagonist prevented these effects. Finally, we performed adoptive cell transfer of Tregs (sorted from FOXP3-GFP females) in VIP-deficient-mice, and we observed that FOXP3-GFP cells were mainly recruited into the uterus/implantation sites compared to all other tested tissues. In addition, after Treg transfer, we found an increase in IL-10 expression and VEGFc in HT females and allowed embryo implantation in KO females. In conclusion, VIP contributes to a local tolerogenic response necessary for successful pregnancy, preventing the development of a hostile uterine microenvironment for implantation by the selective recruitment of Tregs during the peri-implantation period. |
| first_indexed | 2024-12-22T17:20:09Z |
| format | Article |
| id | doaj.art-3724df3d88e04688bd3a950ed0823b54 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T17:20:09Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-3724df3d88e04688bd3a950ed0823b542022-12-21T18:18:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-01-011010.3389/fimmu.2019.02907502984VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic MicroenvironmentLucila Gallino0Vanesa Hauk1Laura Fernández2Elizabeth Soczewski3Soledad Gori4Esteban Grasso5Guillermina Calo6Nora Saraco7Esperanza Berensztein8James A. Waschek9Claudia Pérez Leirós10Rosanna Ramhorst11CONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaServicio de Endocrinología, Hospital Pediátrico Dr. Juan P. Garrahan, CONICET, Universidad de Buenos Aires, Buenos Aires, ArgentinaServicio de Endocrinología, Hospital Pediátrico Dr. Juan P. Garrahan, CONICET, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United StatesCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaCONICET, Laboratorio de Inmunofarmacología, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Universidad de Buenos Aires, Buenos Aires, ArgentinaUterine receptivity and embryo implantation are two main processes that need a finely regulated balance between pro-inflammatory and tolerogenic mediators to allow a successful pregnancy. The neuroimmune peptide vasoactive intestinal peptide (VIP) is a key regulator, and it is involved in the induction of regulatory T cells (Tregs), which are crucial in both processes. Here, we analyzed the ability of endogenous and exogenous VIP to sustain a tolerogenic microenvironment during the peri-implantation period, particularly focusing on Treg recruitment. Wild-type (WT) and VIP-deficient mice [heterozygous (HT, +/−), knockout (KO, −/−)], and FOXP3-knock-in-GFP mice either pregnant or in estrus were used. During the day of estrus, we found significant histological differences between the uterus of WT mice vs. VIP-deficient mice, with the latter exhibiting undetectable levels of FOXP3 expression, decreased expression of interleukin (IL)-10, and vascular endothelial growth factor (VEGF)c, and increased gene expression of the Th17 proinflammatory transcription factor RORγt. To study the implantation window, we mated WT and VIP (+/−) females with WT males and observed altered FOXP3, VEGFc, IL-10, and transforming growth factor (TGF)β gene expression at the implantation sites at day 5.5 (d5.5), demonstrating a more inflammatory environment in VIP (+/−) vs. VIP (+/+) females. A similar molecular profile was observed at implantation sites of WT × WT mice treated with VIP antagonist at d3.5. We then examined the ability GFP-sorted CD4+ cells from FOXP3-GFP females to migrate toward conditioned media (CM) obtained from d5.5 implantation sites cultured in the absence/presence of VIP or VIP antagonist. VIP treatment increased CD4+FOXP3+ and decreased CD4+ total cell migration towards implantation sites, and VIP antagonist prevented these effects. Finally, we performed adoptive cell transfer of Tregs (sorted from FOXP3-GFP females) in VIP-deficient-mice, and we observed that FOXP3-GFP cells were mainly recruited into the uterus/implantation sites compared to all other tested tissues. In addition, after Treg transfer, we found an increase in IL-10 expression and VEGFc in HT females and allowed embryo implantation in KO females. In conclusion, VIP contributes to a local tolerogenic response necessary for successful pregnancy, preventing the development of a hostile uterine microenvironment for implantation by the selective recruitment of Tregs during the peri-implantation period.https://www.frontiersin.org/article/10.3389/fimmu.2019.02907/fullearly pregnancytoleranceVIPtregsimplantation |
| spellingShingle | Lucila Gallino Vanesa Hauk Laura Fernández Elizabeth Soczewski Soledad Gori Esteban Grasso Guillermina Calo Nora Saraco Esperanza Berensztein James A. Waschek Claudia Pérez Leirós Rosanna Ramhorst VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment Frontiers in Immunology early pregnancy tolerance VIP tregs implantation |
| title | VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment |
| title_full | VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment |
| title_fullStr | VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment |
| title_full_unstemmed | VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment |
| title_short | VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment |
| title_sort | vip promotes recruitment of tregs to the uterine placental interface during the peri implantation period to sustain a tolerogenic microenvironment |
| topic | early pregnancy tolerance VIP tregs implantation |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02907/full |
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