VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

Abstract

BackgroundVasoactive 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.MethodsEAE 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.ResultsMOG35–55-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.ConclusionsVPAC1 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0626-3) contains supplementary material, which is available to authorized users.

Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin sst4 Receptor in the Antinociceptive and Anti-inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide

“…Experimental autoimmune encephalomyelitis (EAE) was found to be more severe in PACAP peptide knockout mice ( 49 ). Mirroring our findings on sst4 SOM receptors, animals genetically lacking VPAC1 PACAP receptors exhibited ameliorated responses in the same EAE model and in dextran sulfate-evoked colonic inflammation too ( 50 , 51 ). VPAC1 KO mice had decreased mRNA levels of T h2 cytokines and chemokines ( 50 ).…”

“…Mirroring our findings on sst4 SOM receptors, animals genetically lacking VPAC1 PACAP receptors exhibited ameliorated responses in the same EAE model and in dextran sulfate-evoked colonic inflammation too ( 50 , 51 ). VPAC1 KO mice had decreased mRNA levels of T h2 cytokines and chemokines ( 50 ). A similar compensatory mechanism in sst4 KO animals might influence the activation of neutrophils and macrophages—the dominant cells involved in carrageenan-induced paw edema inflammation—and decrease edema formation ( 52 ).…”

PACAP/PAC1 Regulation of Inflammation via Catecholaminergic Neurons in a Model of Multiple Sclerosis

“…Our laboratory has been investigating immunomodulatory actions of PACAP, VIP, and their receptors in the EAE model using mice globally deficient in these proteins (Abad et al, 2010(Abad et al, , 2016Tan et al, 2009Tan et al, , 2013Tan et al, , 2015. PACAP was originally isolated and shown to induce adenylyl cyclase to produce cyclic AMP in rat pituitary cell cultures (Miyata et al, 1989).…”

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…The results demonstrate stronger Th1 and Th17 responses, which are known to induce the pathogenesis of EAE, but reduced Th2 responses in these mice. As the phenotype of VPAC1 is opposite that of VPAC2-KO mice, it has been suggested that, in addition to Th polarization, other events are differentially mediated by VPAC1 and VPAC2, and this may depend on different factors, such as their level of expression, the state of cellular activation, the interaction with other mediators present in the microenvironment, such as inflammatory factors, and finally, the disease phase [291].…”