NPY in Multiple Sclerosis
Multiple sclerosis is a chronic autoimmune disease of the CNS characterized by multifocal inflammation in the brain, extensive demyelination, axonal loss, and gliosis. Although, the exact pathogenesis of MS remains to be completely elucidated, CD4+T cell-mediated autoimmunity has been accepted as one of the most important aspects of MS pathogenesis (Lazibat et al., 2018). Microglia are resident immune cells in the CNS. In MS microglial are not only involved in CNS damage caused by immune response, but also play an important role in disease recovery and nerve regeneration (Zrzavy et al., 2017). NPY, through its Y1 receptor, can inhibit microglial activation, IL-Iβ production, as well as subsequent NF-κB-iNOS signal transduction, decrease the production of NO (Sørensen et al., 2012). NPY can also reduce the migration and phagocytosis of microglia by limiting the activity of microglia and avoiding excessive release of NO, glutamate, cytokines, and other cytotoxic substances from microglia. This effect is achieved by affecting the p38 signal system. It is also associated with heat shock protein 27 (Ferreira et al., 2012). Remarkably, NPY can inhibit the secretion of IFN-γ and enhance IL-4 secretion of murine lymphocytes, indicating that NPY shifts the help T cell 1 (Th)1/Th2 balance toward the Th2 phenotype (Levite, 2008). It was found that the levels of NPY were decreased in the cerebrospinal fluid of MS patients (Maeda et al., 1994).
Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is an inflammatory autoimmune disease which affects the CNS and is induced by myelin self-antigens (Chen Y. et al., 2019). The suppressive role of exogenous NPY has been demonstrated in EAE mice (Schmitz et al., 2017). Furthermore, Bedoui et al. (2004) tested whether repetitive administrations of NPY would exert any impact on EAE. They found that NPY can ameliorate symptoms and disease severity of EAE in a dose-dependent manner (Schmitz et al., 2017). This effect of NPY presumably occurs by decreasing IFN-γ secretion from autoreactive T lymphocytes and elevating the IgG1-IgG2a ratio of autoantigen-specific antibodies, which indicate that NPY favors Th2 response. When the Y1-receptor signaling was blocked immediately after immunization for EAE, an earlier onset of the disease was observed. This finding indicated that endogenous NPY plays a protective role in EAE induction and exerts its effects directly on T lymphocytes via the NPY Y1 receptor subtype (Schmitz et al., 2017).
The sympathetic nervous system (SNS) is mechanically and functionally affected in both rheumatoid arthritis and MS (Sternberg, 2012). Clinical studies also suggested that the defective crosstalk between SNS and the immune system might further precipitate the manifestations of MS because of considerable SNS dysfunction in patients with MS (Shahabi et al., 2006). Substantial evidence indicated that stress can precipitate or worsen symptoms of inflammation in MS. NPY significantly promoted stress coping and resiliency (Wagner et al., 2016). Neuropeptides secreted under stress could activate microglia and mast cells to release inflammatory molecules. This results in the maturation and activation of Th17 autoimmune cells, destruction of the blood brain barrier (BBB), and T cells entering the CNS, which can promote brain inflammation and cause MS (Karagkouni et al., 2013). These indications give us clues to further investigate the role of NPY in regulating autoimmune processes and to identify a new therapeutic target of MS/EAE.