Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis

Abstract

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.e., VIP KO) mice to myelin oligodendrocyte protein-induced EAE. Surprisingly, VIP KO mice were almost completely resistant to EAE, with delayed onset and mild or absent clinical profile. Despite this, flow cytometric analyses and antigen-rechallenge experiments indicated that myelin oligodendrocyte protein-treated VIP KO mice exhibited robust Th1/ Th17 cell inductions and antigen-specific proliferation and cytokine responses. Moreover, adoptive transfer of lymphocytes from immunized VIP KO mice to WT recipients resulted in full-blown EAE, supporting their encephalitogenic potential. In contrast, transfer of encephalitogenic WT cells to VIP KO hosts did not produce EAE, suggesting that loss of VIP specifically affected the effector phase of the disease. Histological analyses indicated that CD4 T cells entered the meningeal and perivascular areas of VIP-deficient mice, but that parenchymal infiltration was strongly impaired. Finally, VIP pretreatment of VIP KO mice before immunization was able to restore their sensitivity to EAE. These results indicate that VIP plays an unanticipated permissive and/or proinflammatory role in the propagation of the inflammatory response in the CNS, a finding with potential therapeutic relevance in autoimmune neuroinflammatory diseases such as multiple sclerosis.neuropeptide | multiple sclerosis | inflammation T he 28-aa neuropeptide vasoactive intestinal peptide (VIP) was initially discovered in the lung and intestine, where it exhibits potent vasodilator activity (1). It belongs to the secretin family and has high homology to pituitary adenylyl cyclase-activating polypeptide, with which it shares its two high-affinity G proteincoupled receptors (VPAC1 and VPAC2) (2). Widely distributed in neurons in the CNS and periphery, VIP is also present in lymphocytes and innervation within lymphoid organs (3-5). In the immune system, VIP has multiple and complex actions on myeloid and lymphoid cells (6, 7). The fact that VIP inhibits the release of proinflammatory mediators by activated macrophages, promotes Th2 versus Th1 responses, and induces the generation of regulatory T cells (Tregs), suggested that its receptors may be targets for anti-inflammatory drugs. Accordingly, subsequent studies showed that VIP treatment inhibits ongoing inflammatory responses in murine models of septic shock, Crohn's disease, and rheumatoid arthritis (8-11). However, the role of the endogenous peptide in maintaining the balance between potentially harmful and beneficial actions of the immune system r...

Intestinotrophic Glucagon-Like Peptide-2 (GLP-2) Activates Intestinal Gene Expression and Growth Factor-Dependent Pathways Independent of the Vasoactive Intestinal Peptide Gene in Mice

“…The Vip Ϫ/Ϫ mouse exhibits a number of interesting phenotypes, including disturbances of circadian rhythm (27), impaired or enhanced inflammatory responses (37,38), and dysglycemia with abnormal sweet taste preference (39). Very little is known about the basal intestinal phenotype of Vip Ϫ/Ϫ mice; however, increased small bowel weight and smooth muscle thickening, together with increased villous length and reduced staining of mucus in the small bowel has been described in the Vip Ϫ/Ϫ mouse (36).…”

Inhibition of Vasoactive Intestinal Polypeptide (VIP) Induces Resistance to Dextran Sodium Sulfate (DSS)-Induced Colitis in Mice

“…However, in vivo data on the effects of VIP during inflammatory states are not consistent. In a model of EAE (Abad 2010), genetic deletion of VIP resulted in resistance to inflammation with mild or absent clinical signs and lack of CD4 cells infiltration into the brain parenchyma. In another study, VIP −/− mice exhibited resistance to LPS administration with decreased mortality, tissue damage, and pro-inflammatory cytokines (Abad 2012).…”

“…The entry of immune cells into mesenteric lymph nodes and Peyer’s patches is regulated by VPAC1 signaling (Von der Weid 2012). Furthermore, in a model of EAE in VIP −/− mice, T-cells and macrophages accumulated in the subarachnoid space but failed to enter the CNS parenchyma (Abad 2010); the levels of chemokine expression in the CNS were significantly lower in EAE-induced VIP −/− mice. Pharmacological inhibition of VIP in our model was effective in inducing resistance to colitis as that observed in VIP −/− mice.…”

Neuropeptides as Pleiotropic Modulators of the Immune Response

“…PACAP-KO mice show higher incidence and severity of experimental autoimmune encephalomyelitis (EAE), increased inflammatory and Th1-encephalitogenic cells, and decreased antigen-specific Treg cells [87]. Interestingly, the response of VIP-KO mice to EAE results in a delayed onset and mild clinical profile [88]. Although VIP-KO mice exhibited robust Th1/Th17 cell inductions and cytokine responses, showing their increased EAE profile, VIP loss seemed to be involved in the immune infiltration of the nervous parenchyma.…”