NAD+ attenuates experimental autoimmune encephalomyelitis through induction of CD11b+ gr-1+ myeloid-derived suppressor cells.

Jin-Li Wang,Xiao-Li Gai,Ning Zhang,Guo-Jun Tan,Li Guo,Mo-Yuan Quan,Jue-Qiong Wang,Jun-Na Xing,Bin Li

doi:10.1042/bsr20200353

Abstract

Objective: To investigate the effects of nicotinamide adenine dinucleotide (NAD+) on the pathogenesis of the animal model for multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE).Methods: EAE model was induced by myelin oligodendrocyte protein (MOG 35-55). Clinical scores of EAE were measured in mice with or without NAD+ treatment. Hematoxylin and Eosin (HE) and Luxol Fast Blue (LFB) staining were performed to assess inflammation and demyelination, respectively. Expressions of target proteins were measured by Western blot. The numbers of myeloid-derived suppressor cells (MDSCs) were measured by immunofluorescent staining and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the expressions of inflammatory cytokine in serum.Results: NAD+ treatment could decrease inflammatory cells and demyelination foci, attenuate the clinical scores of EAE and slightly delay disease onset. Western blot showed that NAD+ treatment up-regulated the expression of phosphorylated-STAT6 (p-STAT6) and SIRT1. Besides, NAD+ treatment up-regulated the expression of p-IκB and down-regulated the expression of p-NF-κB. In addition, NAD+ treatment could increase the numbers of CD11b+ gr-1+ MDSCs and the expression of Arginase-1. Moreover, NAD+ treatment up-regulated the expressions of IL-13 and down-regulated the expression of IFN-γ and IL-17.Conclusions: The present study demonstrated that NAD+ treatment may induce the CD11b+ gr-1+ MDSCs to attenuate EAE via activating the phosphorylation of STAT6 expression. Therefore, NAD+ should be considered as a potential novel therapeutic strategy for MS.

Highlights

Multiple sclerosis (MS) is a complex chronic autoimmune disease, involving central nervous system (CNS) demyelination and inflammation [1]
These results showed the successful construction of EAE models
After EAE models were treated with NAD+, we observed that the significant increase in demyelination foci and inflammatory cells in the spinal cords of EAE model mice were attenuated by NAD+ treatment (Figure 1A,B)

Summary

Introduction

Multiple sclerosis (MS) is a complex chronic autoimmune disease, involving central nervous system (CNS) demyelination and inflammation [1]. The treatment of MS is mainly anti-inflammatory, but it is only effective in relapse and remission period [4]. Some of these agents (such as Tysabri) may have severe immunosuppressive side effects [5]. Developing novel therapeutic strategies has been an urgent problem for patients with MS. Experimental autoimmune encephalomyelitis (EAE) is the most widely used mouse model of MS, which is mediated by cells of the innate immune system and autoimmune CD4+ T cells [6]. The histopathological and clinical similarities between EAE and MS enable the findings obtained from EAE model to be extrapolated to MS patients [7].

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Discussion

Conclusion