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2. VPAC1 and VPAC2 receptor deficiencies negatively influence pregnancy outcome through distinct and overlapping modulations of immune, trophoblast and vascular functions.

Author

Calo, Guillermina, Hauk, Vanesa, Vota, Daiana, Van, Christina, Gallino, Lucila, Ramhorst, Rosanna, Waschek, James, Pérez Leirós, Claudia, and Condro, Michael

Subjects
Adverse pregnancy outcome models, Innate response at early pregnancy, Placental homeostasis disruption, VPAC1/VPAC2 knockout mice, Animals, Female, Mice, Pregnancy, Placenta, Pregnancy Outcome, Receptors, Vasoactive Intestinal Peptide, Type II, Trophoblasts, Vasoactive Intestinal Peptide, Receptors, Vasoactive Intestinal Polypeptide, Type I, Gene Deletion, Pregnancy Complications
Abstract

Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported. Here we studied the involvement of the two primary high affinity receptors for VIP (VPAC1 and VPAC2) on maternal immune response, placental homeostasis and pregnancy outcome. Targeted disruption of each receptor gene led to altered placental structure, vascular and trophoblast functional markers and shaped the functional profiles of macrophages and neutrophils towards a proinflammatory state. Several changes in pregnant mice were receptor specific: ROS production elicited by VIP on neutrophils was selectively dependent on the presence of VPAC1 whereas apoptosis rate was associated with the VPAC2 deletion. In peritoneal macrophages from pregnant mice, levels of MHC-II, TLR2, and IL-10 were selectively altered in VPAC2 receptor-deficient mice, whereas IL-6 gene expression was reduced only in mice lacking VPAC1 receptors. Additionally, MMP9 mRNA in isolated TGCs was reduced in VPAC2 receptor deleted mice, while the percentage of IL-12 cells in post-phagocytosis macrophage cultures was selectively reduced in VPAC2 receptor deficient mice. The results indicate that manipulation of VPAC1 and VPAC2 receptor affects immune, vascular and metabolic environment at the maternal fetal interface. These mouse models offer new approaches to study pregnancy complications adding new perspectives to the development of VPAC receptor-selective drugs.

Published
2023

7. Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1-driven immune inhibitory circuits

Author

Allo, Verónica C. Martínez, Hauk, Vanesa, Sarbia, Nicolas, Pinto, Nicolás A., Croci, Diego O., Dalotto-Moreno, Tomás, Morales, Rosa M., Gatto, Sabrina G., Cocco, Montana N. Manselle, Stupirski, Juan C., Deladoey, Ángel, Maronna, Esteban, Marcaida, Priscila, Durigan, Virginia, Secco, Anastasia, Mamani, Marta, Dos Santos, Alicia, Pellet, Antonio Catalán, Leiros, Claudia Pérez, Rabinovich, Gabriel A., and Toscano, Marta A.

Published
2020

8. Extracellular Vesicles of Porphyromonas gingivalis Disrupt Trophoblast Cell Interaction with Vascular and Immune Cells in an In Vitro Model of Early Placentation

Author

Lara, Brenda, primary, Sassot, Matías, additional, Calo, Guillermina, additional, Paparini, Daniel, additional, Gliosca, Laura, additional, Chaufan, Gabriela, additional, Loureiro, Iñaki, additional, Vota, Daiana, additional, Ramhorst, Rosanna, additional, Pérez Leirós, Claudia, additional, and Hauk, Vanesa, additional

Published
2023
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10. Placental extracellular vesicles: their potential as biomarkers of gestational complications

Author

Lara, Brenda Ayelen, Merech, Fátima Isabel, Vota, Daiana Marina, Calo, Guillermina, Soczewski, Elizabeth Victoria, Grasso, Esteban Nicolas, Perez Leiros, Claudia, and Hauk, Vanesa Cintia

Subjects
placenta, patologias gestacionales, purl.org/becyt/ford/3 [https], purl.org/becyt/ford/3.1 [https], vesiculas extracelulares
Abstract

Las vesículas extracelulares son importantes mediadores de la comunicación intercelular. Durante la gestación,diversos tipos celulares placentarios como no placentariossecretan vesículas extracelulares a la circulación. Se ha demostrado que las células trofoblásticas liberan permanentemente a la circulación materna vesículas extracelularescargadas con diversas moléculas que modulan la función delas células trofoblásticas, inmunes y vasculares, entre otras.Las complicaciones gestacionales que afectan la placentación, como la restricción del crecimiento intrauterino(RCIU) y la preeclampsia (PE), son un problema de saludpública mundial, ya que son condiciones que contribuyen,en alto grado, a la morbimortalidad materna y neonatal.Hasta ahora, no se dispone de pruebas clínicas quepermitan anticipar el diagnóstico y/o proveer indicadorespredictivos para identificar a las madres con mayor riesgode desarrollar estas complicaciones. En los últimos años,se ha demostrado el potencial de las vesículas extracelulares y su contenido como potenciales biomarcadoresde distintas patologías, por lo que su aplicación despiertaespecial interés en las complicaciones del embarazo. Extracellular vesicles are significant mediators of cellto-cell communication. During pregnancy, placental and non-placental cell types release extracellular vesicles into circulation. Is has been demonstrated that trophoblast cells are continuously releasing vesicles loaded with factors modulating trophoblast, immune and vascular functions. Gestational complications associated to impaired placentation, such as intrauterine growth restriction (IUGR) and preeclampsia (PE), are a global public health problem since they are major contributors to maternal and neonatal morbidity and mortality. Currently, there are no clinical tests that allow early diagnosis and/or provide predictive markers to identify mothers at higher risk of developing these complications. The potential of extracellular vesicles and their content as biomarkers for different pathologies has been demonstrated. For this reason nowadays their application in gestational complications is of special interest. Fil: Lara, Brenda Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Merech, Fátima Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Vota, Daiana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Calo, Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Soczewski, Elizabeth Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Grasso, Esteban Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Perez Leiros, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Hauk, Vanesa Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Published
2020

12. Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1-driven immune inhibitory circuits

Author

Martínez Allo, Verónica C., primary, Hauk, Vanesa, additional, Sarbia, Nicolas, additional, Pinto, Nicolás A., additional, Croci, Diego O., additional, Dalotto-Moreno, Tomás, additional, Morales, Rosa M., additional, Gatto, Sabrina G., additional, Manselle Cocco, Montana N., additional, Stupirski, Juan C., additional, Deladoey, Ángel, additional, Maronna, Esteban, additional, Marcaida, Priscila, additional, Durigan, Virginia, additional, Secco, Anastasia, additional, Mamani, Marta, additional, Dos Santos, Alicia, additional, Catalán Pellet, Antonio, additional, Pérez Leiros, Claudia, additional, Rabinovich, Gabriel A., additional, and Toscano, Marta A., additional

Published
2020
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13. VIP Promotes Recruitment of Tregs to the Uterine–Placental Interface During the Peri-Implantation Period to Sustain a Tolerogenic Microenvironment

Author

Gallino, Lucila, primary, Hauk, Vanesa, additional, Fernández, Laura, additional, Soczewski, Elizabeth, additional, Gori, Soledad, additional, Grasso, Esteban, additional, Calo, Guillermina, additional, Saraco, Nora, additional, Berensztein, Esperanza, additional, Waschek, James A., additional, Pérez Leirós, Claudia, additional, and Ramhorst, Rosanna, additional

Published
2020
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14. Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua

Author

Alippe, Yael, Wang, Leran, Coskun, Reyan, Muraro, Stéfanie P., Zhao, Fang R., Elam-Noll, Michelle, White, J. Michael, Vota, Daiana M., Hauk, Vanesa C., Gordon, Jeffrey I., Handley, Scott A., and Diamond, Michael S.

Abstract

The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1−/− or Mavs−/− placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/− or Ifnar1+/− dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.

Published
2024
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17. Sjögren´s Syndrome: relevance of the VIP/VPAC system to homeostasis maintenane and loss

Author

Hauk, Vanesa Cintia and Pérez Leirós, Claudia

Subjects
CELULAS EPITELIALES DE GLANDULA SUBMAXILAR, REGULATORY MACROPHAGES, GLAND HOMEOSTASIS, FAGOCITOSIS, MACROFAGOS REGULATORIOS, SJÖGREN SYNDROME, GLANDULAR EPITHELIAL CELLS, SINDROME DE SJÖGREN, HOMEOSTASIS GLANDULAR, PEPTIDO INTESTINAL VASOACTIVO, VASOACTIVE INTESTINAL PEPTIDE, PHAGOCYTOSIS
Abstract

El Síndrome de Sjögren (SS) es una enfermedad autoinmune crónica que se caracterizapor una progresiva disfunción secretoria con escasa correlación con el daño tisular enlas glándulas. No hay evidencias claras sobre su patogenia y el tratamiento essintomático con un alivio meramente marginal. Se ha propuesto que previo al ataqueautoinmune hay una pérdida en el equilibrio homeostático de las glándulas conactivación de células acinares que podrían aumentar la susceptibilidad del tejido a unarespuesta autoinmune. Los ratones diabéticos no obesos (NOD) son un modelo muyinteresante para estudiar el SS ya que desarrollan una disfunción secretoria conpérdida de temprana de la homeostasis glandular con una moderada infiltraciónlinfocitaria. Los macrófagos, son células plásticas, que tienen un papel central en elmantenimiento de la homeostasis tisular por su función fagocítica para la remoción deproductos de degradación y células apoptóticas, función que realizan en forma ‘silenciosa’ y rápida evitando una respuesta inflamatoria deletérea. El péptidointestinal vasoactivo (VIP) es un neurotransmisor autonómico pro‐secretorio yvasodilatador, que tiene efecto trófico sobre acinos y, junto a sus receptores VPAC, selocaliza en células inmunes con un marcado efecto anti‐inflamatorio einmunomodulador. Basados en los efectos pro‐secretorios y tróficos del VIP sobre los acinos como de suspropiedades anti‐inflamatorias hipotetizamos que la liberación local de VIP pordiversos tipos celulares podría modular procesos apoptóticos e inflamatorios en lainteracción de células inmunes con células epiteliales contribuyendo al mantenimientode la homeostasis tisular glandular. Asimismo, hipotetizamos que estos mecanismosmodulados por VIP se verían alterados en condiciones de ruptura de la homeostasistisular. En este trabajo en primer lugar se estudio el papel del VIP en el mantenimiento de lahomeostasis glandular en el modelo murino NOD. Se observo que hay una disminuciónen la expresión de VIP en las glándulas salivales de ratones NOD que no se observa enla cepa control. La pérdida en la expresión del VIP endógeno se ve asociada con lapérdida de células acinares. Por otro lado, el ‘clearance’ de acinos apoptóticos pormacrófagos se encuentra desregulado en los macrófagos NOD. Sin embargo durante elproceso fagocítico dichos macrófagos adquieren un perfil alternativo de activación. Finalmente, se analizó la contribución del sistema VIP/VPAC en un modelo in vitro deco‐cultivo de células mononucleares totales o monocitos de pacientes con síndrome de Sjögren y células epiteliales de glándula submaxilar (HSG). En primer lugarcaracterizamos el sistema VIP/VPAC en monocitos y su capacidad fagocítica de células HSG apoptóticas donde observamos que los monocitos de pacientes con SS presentanincrementada la expresión del receptor VPAC2 ausente en los monocitos controles y sucapacidad fagocítica se ve alterada. No solo fagocitan en menor cantidad sino queadquieren un perfil fenotípico inflamatorio que no puede ser modulado por VIP. En losco‐cultivos se estudió el perfil funcional y fenotípico de ambos tipos celulares luego dela interacción. Nuestros resultados indican que la interacción puede modular tanto alas células epiteliales como a los monocitos contribuyendo a la generación de unmicroambiente proinflamatorio, donde el VIP fue capaz de modular parcialmentedicho microambiente. Sjögren’s Syndrome (SS) is a chronic autoimmune disease characterized by a deepsecretory dysfunction that correlates poorly with moderate gland damage. SSpathogenesis is still not clearly elucidated and the treatment is symptomatic. It hasbeen proposed that homeostatic loss and acinar activation in the glands precedes theautoimmune response. Non obese diabetic mice (NOD) are a suitable model to study SS since they develop secretory dysfunction with early gland homeostasis loss and amoderate mononuclear infiltration of submandibular glands. Macrophages are plasticcells with a central role in tissue homeostasis maintenance due to their phagocyticfunction to ‘silently’ and rapidly remove apoptotic cells to prevent an inflammatorydeleterious response. Vasoactive intestinal peptide (VIP) is an autonomicneurotransmitter with secretory and vasodilator effects that exerts trophic effects onacini and, along with its VPAC receptors, localizes in immune cells with a strong anti‐inflammatory and immunomodulatory effect. Based on the pro‐secretory and trophic activities of VIP on acini as well as its anti‐inflammatory effect we hypothesized that the local release of VIP by various cell typescould modulate inflammatory and apoptotic processes at the immune‐epithelial cellinteraction contributing to tissue homeostasis maintenance. We hypothesized thatthese VIP‐modulated mechanisms could be altered in homeostasis loss conditions. In this work we first studied the role of VIP in gland homeostasis maintenance in the NOD model. We observed a reduced expression of VIP in salivary glands of NOD micecompared with control mice. The loss of VIP expression was associated with reducednumber of acini. Moreover, apoptotic cell clearance by NOD macrophages wasdefective but the cells acquired an alternative activation profile after phagocytosis. Finally, the contribution of VIP/VPAC system in an in vitro model of immune‐epithelialinteraction was assessed. We co‐cultured PBMC or monocytes from individual SSpatients or control subjects with epithelial cells from a human salivary gland (HSG line). First, we characterized VIP/VPAC system in monocytes and phagocytosis of HSGapoptotic epitelial cells. An increased expression of VPAC2 and reduced phagocytosisof apoptotic cells was found only in SS monocytes. These monocytes also failed toexpress an anti‐inflammatory response upon phagocytosis of apoptotic cells. Thefunctional and phenotypic profile of both epithelial cell and monocytes uponinteraction was then studied. Our results indicate that the interaction can modulateboth epithelial cells and monocytes contributing to the generation of a pro‐inflammatory microenvironment where VIP could only partially modulate thesesignals. Fil: Hauk, Vanesa Cintia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Published
2015

26. Vasoactive intestinal peptide induces metabolic rewiring of human-derived cytotrophoblast cells to promote cell migration.

Author

Merech F, Lara B, Rios D, Paparini D, Ramhorst R, Hauk V, Pérez Leirós C, and Vota D

Abstract

The placenta has an extraordinary metabolic rate with high oxygen consumption. Extravillous cytotrophoblast cells (EVT) metabolism and function are critical to sustain their invasive phenotype supporting fetal development. Deficient EVT function underlies pregnancy complications as preeclampsia (PE) and fetal growth restriction (FGR). The vasoactive intestinal peptide (VIP) promotes human cytotrophoblast cell migration and invasion through mTOR signaling pathways suggesting its crucial role during placentation. Here we explored fatty acid uptake as well as lipid and glucose metabolism in human-derived cytotrophoblast cell function upon VIP stimulation. We found that VIP induced long chain fatty acid (LCFAs) uptake along with the expression of FATP2 transporter, CPT1 fatty acid oxidation (FAO)-rate limiting step importer, and lipid droplet accumulation. VIP induced the expression of glucose 6-P-dehydrogenase, a rate-limiting enzyme of the pentose phosphate pathway (PPP) and pyruvate dehydrogenase complex enzyme DLAT E2, without altering lactate secretion. This metabolic rewiring of trophoblast cells induced by VIP takes place without compromising mitochondrial function or reactive oxygen species (ROS) production. Moreover, cytotrophoblast cell migration induced by VIP required the three glycolysis, oxidative phosphorylation (OXPHOS) and FAO pathways. Our results provide evidence supporting VIP as a metabolic regulatory peptide in cytotrophoblast cells sustaining proper placentation and fetal growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2024
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27. Trophoblast cells primed with vasoactive intestinal peptide enhance monocyte migration and apoptotic cell clearance through αvβ3 integrin portal formation in a model of maternal-placental interaction.

Author

Paparini D, Grasso E, Calo G, Vota D, Hauk V, Ramhorst R, and Leirós CP

Subjects
Apoptosis drug effects, Female, Humans, Monocytes metabolism, Placenta drug effects, Placenta metabolism, Pregnancy, Trophoblasts drug effects, Vasoactive Intestinal Peptide pharmacology, Integrin alphaVbeta3 metabolism, Trophoblasts metabolism
Abstract

Study Hypothesis: Is apoptotic cell phagocytosis by monocytes modulated by pathways elicited by vasoactive intestinal peptide (VIP) action on trophoblast?, Study Finding: Targeting trophoblast cells with VIP induces monocyte migration, polarization to anti-inflammatory phenotypes and apoptotic trophoblast cell clearance which involves increased αvβ3 integrin expression on phagocytic cells and binding to thrombospondin 1., What Is Known Already: Monocytes recruited to the maternal-placental interface interact with trophoblast cells and differentiate to alternatively activated macrophages involved in the silent clearance of apoptotic cells. Vasoactive intestinal peptide (VIP) is an immunomodulatory polypeptide synthesized at the human placenta that can target both trophoblast cells and monocytes/macrophages. Integrin αvβ3 and thrombospondin 1 are involved in the formation of a phagocytic portal for the immunosuppressant clearance of apoptotic cells., Study Design, Samples/materials, Methods: This is a laboratory-based study studying monocytes isolated from peripheral blood of healthy women (n = 33) and their interaction in vitro with first trimester trophoblast cell lines. Peripheral blood monocytes were isolated from healthy volunteers by Percoll gradient and tested in co-culture settings with first trimester trophoblast cell lines (Swan 71 and HTR8) or with trophoblast cell conditioned media obtained in the presence or absence of 10 or 100 nM VIP. The effect of VIP-conditioned media on monocyte migration was assessed through transwell systems and monocyte/macrophage phenotype was determined by flow cytometry. Phagocytosis of apoptotic cells and the mechanisms involved in phagocytic portal formation were assessed by flow cytometry, confocal microscopy, immunological blockade and RT-PCR., Main Results and the Role of Chance: Exposing cells to 100 nM VIP increased the migration of monocytes toward trophoblast cell conditioned media (VIP conditioned medium) (P < 0.05 versus conditioned media from cells not exposed to VIP) and contributed to the monocytes acquiring an anti-inflammatory profile with increased CD39 and IL-10 expression (P < 0.05). Phagocytosis of apoptotic trophoblast cells by monocytes and monocyte-differentiated macrophages was increased by VIP conditioned medium (P < 0.05 versus media conditioned in the absence of VIP or direct addition of 100 nM VIP). The boosting effect of VIP conditioned medium on phagocytosis involved increased expression and re-localization of αvβ3 integrin on phagocytic cells along with enhanced expression of thrombospondin 1 on trophoblast cells., Limitations, Reasons for Caution: The conclusions are based on in vitro experiments with monocytes drawn from peripheral blood of healthy individuals and trophoblast cell lines and we were unable to ascertain that these mechanisms operate similarly in vivo. We cannot rule out a differential behavior of either trophoblast cells targeted in vivo with VIP, or primary cultures of first trimester trophoblast cells assayed in vitro., Wider Implications of the Findings: The results presented provide new clues for immune and trophoblast cell pharmacological targeting in pregnancy complications of immunopathologic nature., Study Funding/competing Interests: This work was funded by the National Agency of Sciences and Technology ANPCyT (PICT 2011-0144), National Research Council CONICET (PIP 602/2012) and University of Buenos Aires (UBACyT 20020130100040BA) to C.P.L. The authors have no conflicts of interest to disclose., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2015
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28. Vasoactive intestinal peptide inhibits TNF-alpha-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands.

Author

Calafat M, Larocca L, Roca V, Hauk V, Pregi N, Nesse A, and Pérez Leirós C

Subjects
Animals, Blotting, Western, Cyclic AMP-Dependent Protein Kinases metabolism, Disease Models, Animal, Female, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction physiology, Sjogren's Syndrome pathology, Submandibular Gland pathology, Apoptosis physiology, Sjogren's Syndrome metabolism, Submandibular Gland metabolism, Tumor Necrosis Factor-alpha metabolism, Vasoactive Intestinal Peptide metabolism
Abstract

Introduction: The role of apoptotic secretory epithelium as a pro-inflammatory triggering factor of exocrine dysfunction is currently explored in Sjogren's syndrome patients and in the nonobese diabetic (NOD) mouse model. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects in various models of chronic inflammation. Our goal was to analyse the effect of TNF-alpha on apoptotic mediators in isolated acinar cells from NOD submandibular gland and their modulation by VIP., Methods: Acinar cells were isolated from submandibular glands of 16-week-old NOD females with salivary flow decline. Age-matched BALB/c females or eight-week-old NOD females were used as controls. Apoptotic mediators and TNF-alpha receptor expression were assessed by immunoblotting and RT-PCR, caspase 3 activity was assessed by optical density at 405 nm with Ac-DEVD-pNA as a substrate and chromatin condensation by Hoechst stain. They were evaluated in resting conditions and after a 3.5 or 6 hours of culture with TNF-alpha. VIP effects in acinar cells were assessed at 100 nM in TNF-alpha-treated cultures and VIP receptor functional assays by radio immunoassay (cAMP) or enzymatic detection (amylase)., Results: NOD acinar cells at 16 weeks present an increased expression of TNF-alpha receptor1 together with increased Bax, tumour protein 53-induced nuclear protein1alpha (TP53INP1alpha), caspase 3 activity and chromatin condensation. Acini from NOD mice were more sensitive to TNF-alpha-induced increases of apoptotic mediators than control cells. VIP inhibited TNF-alpha-induced apoptotic events through functional VPAC1 receptors coupled to the protein kinase A (PKA) signalling pathway., Conclusions: Our results indicate that acinar cells isolated from submandibular glands of NOD mice with salivary dysfunction are more sensitive to apoptosis induced by TNF-alpha which could be prevented by VIP through a PKA-mediated pathway.

Published
2009
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