Mechanism Of The Therapeutic Effects Of Spermidine On Experimental Autoimmune Encephalomyelitis Via Macrophage

An autoimmune disease occurs when the immune system attacks and destroys healthy self-tissue by mistake.There are more than 80 kinds of autoimmunediseases have been characterized.Multiple sclerosis(MS)is one of the chronic and debilitating autoimmune diseases,characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction.Spermidine,a natural polyamine,is one of the metabolites of arginine.Spermidine has been shown to affect inflammation in some experimental models.In this study,we investigated the regulatory role of spermidine on MS,and unveiled an identified therapeutic potential of spermidine on autoimmune diseases.We show here that spermidine could alleviate experimental autoimmuneencephalomyelitis(EAE),a model for MS.The treatment with spermidine inhibits the immune responses andreduces the infiltration of CD4~+T cells andmacrophages in central nervous system.The immunosuppression effect ofspermidine on EAE is leaded by regulation of macrophages rather than directinhibition of pathogenic T cells.This point is supported by a series of evidence.We found that spermidine treatment of MOG-specific T cells did not affect theirpathogenic potency upon adaptive transfer,however;depletion of macrophages in diseased mice completely abolished the therapeutic effect of spermidine;spermidine diminished the ability of macrophages in activating MOG-specific Tcells ex vivo.Thus,spermidine exerts its immunosuppressionrole on EAE through regulating the function of macrophages,which subsequently inhibit the activation and proliferation of pathogenic T cells.Mechanistically,two pathways were identified involving in the regulation ofspermidine on macrophages.On the one hand,spermidine inhibit NF-κB signaling by impacting the phosphorylation and degradation of IκB,and also by suppressing phosphorylation of p65 at Ser536,which is required by the transactivation activity of p65.NF-κB transactivates several inflammatory cytokines and co-stimulatorymolecules that are‘second signals’required for T cell activation.Thus,spermidine endow macrophages with immunosuppression through inhibiting NF-κB signaling.On the other hand,by gene expression array analysis,expression arginase I was found increased in macrophages by spermidine treatment.It has been reported that arginase I in macrophages modulates the TCR co-receptor CD3ξchain and impacts the activation of T cells;high level of arginase 1 could also deplete thearginine in the microenvironment,and hinder the activation and proliferation of T cells.Interestingly,macrophages from spermidine treated mice could also reverse EAE progression,while pretreatment of those macrophages with the arginase 1inhibitor abrogated the therapeutic effect.Thus,arginase I is required for theregulatory role of spermidine on macrophages.Therefore,our studies revealed a critical role of macrophages inspermidine-mediated treatment on EAE and provided novel information for better management of MS.