Spermine alleviates experimental autoimmune encephalomyelitis via regulating T cell activation and differentiation

Multiple sclerosis (MS) is a chronic neuroinflammatory disease which causes demyelination, axonal damage and even disability. Th1 and Th17 cells, more precisely, the IFNγ/IL17a double producing CD4⁺ T cells, have been known to play critical roles in the pathogenesis of MS and EAE, a mouse model of MS. Polyamines not only regulate the immune system, but also are essential for the normal function of the central nervous system (CNS). In this study, we demonstrate that the supplementation of spermine (SPM), a biogenic polyamine, significantly suppresses EAE progression in both preventative and therapeutic ways. Further study suggests that spermine significantly reduces IFNγ⁺/IL17a^-, IFNγ^-/IL17a⁺ and IFNγ⁺/IL17a⁺ cells in periphery, and thus reducing the infiltration of these pathogenic cells into the CNS. In vitro, spermine has been shown to suppress the activation and proliferation of CD4⁺ T cells and also significantly impede the polarization of T effector cells in a dose-dependent manner, accompanied by the inhibition of ERK phosphorylation. Consistently, a number of MEK/ERK inhibitors (including PD0325901, FR180204 and selumetinib) have been found to mimic the effects of spermine in inhibiting CD4⁺ T cell activation and T effector cell differentiation. Collectively, spermine alleviates EAE progression by inhibiting CD4⁺ T cells activation and T effector cell differentiation in a MAPK/ERK-dependent manner, suggesting this pathway might be a target to develop effective therapies for MS.