Oleanolic Acid Acetate Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis in Mice by Regulating Toll-Like Receptor 2 Signaling.

Minju Kim,Kyungsook Jung,Jihye Lee,In-Chul Lee,Soyoung Lee,Jeongtae Kim,Hyungjin Lim,Mun-Chual Rho,Ginnae Ahn,Taekyun Shin,Hyung-Jun Kwon,Young-Bae Ryu,Ji-Young Park

doi:10.3389/fphar.2020.556391

Abstract

Toll-like receptor 2 (TLR2) is expressed by several immune cells in the central nervous system and plays an important role in neuroinflammation. TLR2 upregulation has been reported in multiple sclerosis patients and in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Therefore, modulating TLR2 signaling can be an effective treatment strategy against MS. Oleanolic acid acetate (OAA) has antiinflammatory and immunomodulatory effects. Hence, this study aimed to examine the effects of OAA on TLR2 signaling and neuroinflammation in EAE. EAE was induced in C57/BL6 mice using synthesized myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, and OAA was administered daily. Hind limb paralysis and inflammatory cell infiltration were observed in the spinal cords of EAE mice. Moreover, T-cell proliferation was significantly stimulated in splenic cells from EAE mice. The expression of proinflammatory cytokines in the spinal cord was upregulated, and their serum protein levels were increased in EAE mice. Furthermore, upregulation of TLR2 and downstream signaling molecules was observed in the spinal cord. These pathological changes were reversed by OAA treatment. Our results suggest that OAA might have promising therapeutic properties and that the TLR signaling pathway is an effective therapeutic target against multiple sclerosis.

Highlights

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS)
Since Toll-like receptor 2 (TLR2) signaling plays an important role in the pathogenesis of EAE, and the effects of Oleanolic acid acetate (OAA) on TLR2 signaling have not been studied, we aimed to investigate the effects of OAA on neuroinflammation and TLR2 signaling in a mouse model of EAE
Protein levels of TNF receptorassociated factor 6 (TRAF6) and p-IKBa were lower in OAA-treated mice than in vehicle-treated EAE mice (Figure 5B). These results suggest that OAA treatment in EAE mice mitigated the inflammatory response by regulating TLR2induced myeloid differentiation primary response protein 88 (MyD88) signaling in the spinal cords (Figure 5)

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Inflammatory cytokines secreted by these macrophages damage the myelin and axons, activating an inflammatory cascade in the CNS (Constantinescu et al, 2011). Toll-like receptors (TLRs) are widely expressed by several immune cells, such as dendritic cells, T cells, B cells, monocytes, and macrophages. They play an important role in the innate immune since various stimulators, such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), induce lymphocyte activation (Keogh and Parker, 2011) and neuroinflammation through TLRs (Vijay, 2018; Kumar, 2019). TLR2 expression is up-regulated in oligodendrocytes, peripheral blood mononuclear cells, cerebrospinal fluid mononuclear cells, and demyelinating lesions of MS patients (Miranda-Hernandez and Baxter, 2013; Hasheminia et al, 2014; Hossain et al, 2018)

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