Rapamycin Alleviates the Symptoms of Multiple Sclerosis in Experimental Autoimmune Encephalomyelitis (EAE) Through Mediating the TAM-TLRs-SOCS Pathway.

Xiao-Ling Li,Man-Xia Wang,Bo Zhang,Meng-Jiao Sun,Ya-Lan Zhang,Wei Liu,Hui Liu

doi:10.3389/fneur.2020.590884

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Our research aimed to find an immunomodulatory therapy for MS. An experimental autoimmune encephalomyelitis (EAE) mouse model of MS was established induced with the syntheticmyelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Fifty C57BL/6 mice were randomly divided into the Normal group, EAE group, and Rapamycin group (EAE mice treated with three different doses of rapamycin). Hematoxylin and eosin staining and Weil myelin staining were performed on the brain tissues of mice after 21 days post-immunization. The protein expression of Gas6, Tyro3, Axl, Mer in paraventricular tissues were analyzed by immunohistochemistry. The mRNA and protein expression of Gas6, Tyro3, Axl, Mer, SOCS1, SOCS3, Toll-like receptor (TLR) 3, and TLR4 were detected by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of the inflammatory factors IFN-γ and IL-17. Rapamycin treatment could ameliorate the behavior impairment in EAE mice induced by MOG35-55. The expression of Gas6, Tyro3, Axl, Mer, SOCS1, and SOCS3 were decreased in EAE mice at 21 days post-immunization, while the expression of Gas6, Tyro3, Axl, and Mer in rapamycin group was higher than that in EAE group. It was accompanied by an increase in anti-inflammatory proteins SOCS1 and SOCS3, a decrease in the inflammatory proteins TLR-3, TLR-4 and in the amount of IFN-γ, and IL-17. Rapamycin injection relieved the nerve function of and the loss of myelin sheath in the EAE mice, mainly through mediating the TAM-TLRs-SOCS signaling pathway to regulate natural immunity.

Highlights

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS)
The body weights of low-dose, medium-dose, and high-dose rapamycin groups were increased when compared with EAE group during study period (30 days) (P < 0.001, Figure 1A)
These results demonstrated that rapamycin treatment can ameliorate the behavior impairment in EAE mice induced by MOG35-55

Summary

Introduction

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). Remission-relapse is a key clinical characteristic of the disease [1]. The treatment of MS includes acute episode therapy and immunomodulatory therapy. Reducing the recurrence rate remains a significant challenge to the treatment of MS. Multiple Sclerosis and TAM-TLRs-SOCS therapies of the first generation, including interferon-β (IFNβ) and glatiramer acetate, have become the standard of care in relapsing-remitting MS [2]. There are not enough immunomodulatory drugs such as trifluramine and IFN-β to control the recurrence of MS, and they are considerably high cost [3]. New drugs for MS therapy still need to be developed

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