Neuropeptide Y (NPY) Suppresses Experimental Autoimmune Encephalomyelitis: NPY1 Receptor-Specific Inhibition of Autoreactive Th1 Responses In Vivo

Abstract

Prior studies have revealed that the sympathetic nervous system regulates the clinical and pathological manifestations of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model mediated by Th1 T cells. Although the regulatory role of catecholamines has been indicated in the previous works, it remained possible that other sympathetic neurotransmitters like neuropeptide Y (NPY) may also be involved in the regulation of EAE. Here we examined the effect of NPY and NPY receptor subtype-specific compounds on EAE, actively induced with myelin oligodendrocyte glycoprotein 35–55 in C57BL/6 mice. Our results revealed that exogenous NPY as well as NPY Y1 receptor agonists significantly inhibited the induction of EAE, whereas a Y5 receptor agonist or a combined treatment of NPY with a Y1 receptor antagonist did not inhibit signs of EAE. These results indicate that the suppression of EAE by NPY is mediated via Y1 receptors. Furthermore, treatment with the Y1 receptor antagonist induced a significantly earlier onset of EAE, indicating a protective role of endogenous NPY in the induction phase of EAE. We also revealed a significant inhibition of myelin oligodendrocyte glycoprotein 35–55-specific Th1 response as well as a Th2 bias of the autoimmune T cells in mice treated with the Y1 receptor agonist. Ex vivo analysis further demonstrated that autoimmune T cells are directly affected by NPY via Y1 receptors. Taken together, we conclude that NPY is a potent immunomodulator involved in the regulation of the Th1-mediated autoimmune disease EAE.

Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin

“…The CD4 ϩ T cells from ghrelin-treated mice did not differ from those from saline-treated mice in the ability to mediate passive EAE, indicating that ghrelin does not primarily affect induction of encephalitogenic CD4 ϩ T cells in vivo. While NPY attenuates EAE by a Th2 bias of encephalitogenic CD4 ϩ T cells (29), our findings likely suggest that ghrelin interacts independently of NPY in the amelioration of EAE.…”

“…In contrast, NPY is increased after starvation. Exogenous NPY would shift the Th1/Th2 balance toward Th2 and can ameliorate the severity of EAE (29). Interestingly, both peptide hormones are linked to ghrelin in an endocrine feedback system (30).…”

“…Leptin and NPY both influence the Th1/Th2 balance in opposing directions (27)(28)(29). Since ghrelin is the most potent NPY-releasing hormone and NPY suppresses EAE by a Th2 bias (29), we examined whether ghrelin affects the Th1/Th2 balance similar to NPY and if its potential mechanism of EAE suppression is primarily mediated on immune cells or secondarily through NPY release.…”

Multiple loci comprising immune-related genes regulate experimental neuroinflammation

“…Neuropeptide Y is a further potential candidate within Eae25, which ameliorates symptoms of EAE. 47 In the case of Eae26, there are some interesting candidates in the interval such as Ig kappa light-chain genes. Elevated values of kappa light chains in the cerebrospinal fluid are proposed to correlate with disability in MS. 48 Perhaps even more attractive candidates, for the central role in EAE pathogenesis, are the genes that encode IL-12 receptor-b 2 49 and IL-23 receptor, 50 which mapped to Eae26.…”

A vulnerability locus to multiple sclerosis maps to 7p15 in a region syntenic to an EAE locus in the rat

“…Very recently, NPY was shown to be a potent immunomodulator able to induce a Th2 shift in vitro and to suppress significantly the clinical course of EAE. 23 Given that the levels of NPY in the cerebrospinal fluid of MS patients are reduced, 24 it is tempting to speculate that NPY may also play a critical role in preventing the development of MS. These candidate genes should therefore be examined in priority.…”