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VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage.
J Neuroinflammation. 2016 06 29; 13(1):169.JN

Abstract

BACKGROUND

Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two highly homologous neuropeptides. In vitro and ex vivo experiments repeatedly demonstrate that these peptides exert pronounced immunomodulatory (primarily anti-inflammatory) actions which are mediated by common VPAC1 and VPAC2 G protein-coupled receptors. In agreement, we have shown that mice deficient in PACAP ligand or VPAC2 receptors exhibit exacerbated experimental autoimmune encephalomyelitis (EAE). However, we observed that VIP-deficient mice are unexpectedly resistant to EAE, suggesting a requirement for this peptide at some stage of disease development. Here, we investigated the involvement of VPAC1 in the development of EAE using a VPAC1-deficient mouse model.

METHODS

EAE was induced in wild-type (WT) and VPAC1 knockout (KO) mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), and clinical scores were assessed continuously over 30 days. Immune responses in the spinal cords were determined by histology, real-time PCR and immunofluorescence, and in the draining lymph nodes by antigen-recall assays. The contribution of VPAC1 expression in the immune system to the development of EAE was evaluated by means of adoptive transfer and bone marrow chimera experiments. In other experiments, VPAC1 receptor analogs were given to WT mice.

RESULTS

MOG35-55-induced EAE was ameliorated in VPAC1 KO mice compared to WT mice. The EAE-resistant phenotype of VPAC1 KO mice correlated with reduced central nervous system (CNS) histopathology and cytokine expression in the spinal cord. The immunization phase of EAE appeared to be unimpaired because lymph node cells from EAE-induced VPAC1 KO mice stimulated in vitro with MOG exhibited robust proliferative and Th1/Th17 responses. Moreover, lymph node and spleen cells from KO mice were fully capable of inducing EAE upon transfer to WT recipients. In contrast, WT cells from MOG-immunized mice did not transfer the disease when administered to VPAC1 KO recipients, implicating a defect in the effector phase of the disease. Bone marrow chimera studies suggested that the resistance of VPAC1-deficient mice was only minimally dependent on the expression of this receptor in the immunogenic/hematopoietic compartment. Consistent with this, impaired spinal cord inductions of several chemokine mRNAs were observed in VPAC1 KO mice. Finally, treatment of WT mice with the VPAC1 receptor antagonist PG97-269 before, but not after, EAE induction mimicked the clinical phenotype of VPAC1 KO mice.

CONCLUSIONS

VPAC1 gene loss impairs the development of EAE in part by preventing an upregulation of CNS chemokines and invasion of inflammatory cells into the CNS. Use of VPAC1 antagonists in WT mice prior to EAE induction also support a critical role for VPAC1 signaling for the development of EAE.

Authors+Show Affiliations

Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA. Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France.Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA.Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France.Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA.Department of Pediatrics and Holden Comprehensive Cancer Center, RJ and LA Carver College of Medicine, University of Iowa, Iowa City, 52242, IA, USA.Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA.Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, USA. yossan-var.tan@inserm.fr. Inserm U905, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Normandy, France. yossan-var.tan@inserm.fr.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27357191

Citation

Abad, Catalina, et al. "VPAC1 Receptor (Vipr1)-deficient Mice Exhibit Ameliorated Experimental Autoimmune Encephalomyelitis, With Specific Deficits in the Effector Stage." Journal of Neuroinflammation, vol. 13, no. 1, 2016, p. 169.
Abad C, Jayaram B, Becquet L, et al. VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. J Neuroinflammation. 2016;13(1):169.
Abad, C., Jayaram, B., Becquet, L., Wang, Y., O'Dorisio, M. S., Waschek, J. A., & Tan, Y. V. (2016). VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. Journal of Neuroinflammation, 13(1), 169. https://doi.org/10.1186/s12974-016-0626-3
Abad C, et al. VPAC1 Receptor (Vipr1)-deficient Mice Exhibit Ameliorated Experimental Autoimmune Encephalomyelitis, With Specific Deficits in the Effector Stage. J Neuroinflammation. 2016 06 29;13(1):169. PubMed PMID: 27357191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. AU - Abad,Catalina, AU - Jayaram,Bhavaani, AU - Becquet,Laurine, AU - Wang,Yuqi, AU - O'Dorisio,M Sue, AU - Waschek,James A, AU - Tan,Yossan-Var, Y1 - 2016/06/29/ PY - 2016/01/04/received PY - 2016/06/14/accepted PY - 2016/7/1/entrez PY - 2016/7/1/pubmed PY - 2017/10/7/medline KW - Experimental autoimmune encephalomyelitis KW - Multiple sclerosis KW - Neuroimmunomodulation KW - Neuropeptide KW - VPAC1 SP - 169 EP - 169 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 13 IS - 1 N2 - BACKGROUND: Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two highly homologous neuropeptides. In vitro and ex vivo experiments repeatedly demonstrate that these peptides exert pronounced immunomodulatory (primarily anti-inflammatory) actions which are mediated by common VPAC1 and VPAC2 G protein-coupled receptors. In agreement, we have shown that mice deficient in PACAP ligand or VPAC2 receptors exhibit exacerbated experimental autoimmune encephalomyelitis (EAE). However, we observed that VIP-deficient mice are unexpectedly resistant to EAE, suggesting a requirement for this peptide at some stage of disease development. Here, we investigated the involvement of VPAC1 in the development of EAE using a VPAC1-deficient mouse model. METHODS: EAE was induced in wild-type (WT) and VPAC1 knockout (KO) mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), and clinical scores were assessed continuously over 30 days. Immune responses in the spinal cords were determined by histology, real-time PCR and immunofluorescence, and in the draining lymph nodes by antigen-recall assays. The contribution of VPAC1 expression in the immune system to the development of EAE was evaluated by means of adoptive transfer and bone marrow chimera experiments. In other experiments, VPAC1 receptor analogs were given to WT mice. RESULTS: MOG35-55-induced EAE was ameliorated in VPAC1 KO mice compared to WT mice. The EAE-resistant phenotype of VPAC1 KO mice correlated with reduced central nervous system (CNS) histopathology and cytokine expression in the spinal cord. The immunization phase of EAE appeared to be unimpaired because lymph node cells from EAE-induced VPAC1 KO mice stimulated in vitro with MOG exhibited robust proliferative and Th1/Th17 responses. Moreover, lymph node and spleen cells from KO mice were fully capable of inducing EAE upon transfer to WT recipients. In contrast, WT cells from MOG-immunized mice did not transfer the disease when administered to VPAC1 KO recipients, implicating a defect in the effector phase of the disease. Bone marrow chimera studies suggested that the resistance of VPAC1-deficient mice was only minimally dependent on the expression of this receptor in the immunogenic/hematopoietic compartment. Consistent with this, impaired spinal cord inductions of several chemokine mRNAs were observed in VPAC1 KO mice. Finally, treatment of WT mice with the VPAC1 receptor antagonist PG97-269 before, but not after, EAE induction mimicked the clinical phenotype of VPAC1 KO mice. CONCLUSIONS: VPAC1 gene loss impairs the development of EAE in part by preventing an upregulation of CNS chemokines and invasion of inflammatory cells into the CNS. Use of VPAC1 antagonists in WT mice prior to EAE induction also support a critical role for VPAC1 signaling for the development of EAE. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/27357191/VPAC1_receptor__Vipr1__deficient_mice_exhibit_ameliorated_experimental_autoimmune_encephalomyelitis_with_specific_deficits_in_the_effector_stage_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0626-3 DB - PRIME DP - Unbound Medicine ER -