Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release.

Yan Sun,Yong Xu,Jiapei Dai,Zhengrong Han,Ping Xiong,Weitai Chai,Huoying Chen,Zhongjun Wan,Feili Gong,Fang Zheng

doi:10.3389/fimmu.2018.01518

Abstract

The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE). Glycyrrhizin (GL), a glycoconjugated triterpene extracted from licorice root, has the ability to inhibit the functions of HMGB1; however, GL’s function against EAE has not been thoroughly characterized to date. To determine the benefit of GL as a modulator of neuroinflammation, we used an in vivo study to examine GL’s effect on EAE along with primary cultured cortical neurons to study the GL effect on HMGB1 release. Treatment of EAE mice with GL from onset to the peak stage of disease resulted in marked attenuation of EAE severity, reduced inflammatory cell infiltration and demyelination, decreased tumor necrosis factor-alpha (TNF-α), IFN-γ, IL-17A, IL-6, and transforming growth factor-beta 1, and increased IL-4 both in serum and spinal cord homogenate. Moreover, HMGB1 levels in different body fluids were reduced, accompanied by a decrease in neuronal damage, activated astrocytes and microglia, as well as HMGB1-positive astrocytes and microglia. GL significantly reversed HMGB1 release into the medium induced by TNF-α stimulation in primary cultured cortical neurons. Taken together, the results indicate that GL has a strong neuroprotective effect on EAE mice by reducing HMGB1 expression and release and thus can be used to treat central nervous system inflammatory diseases, such as MS.

Highlights

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the central nervous system (CNS) [1]
Strategy I injection occurred from days −1 to day 11, which we refer to as early GL treatment; strategy II injection was from days 12 to 22 as the midterm-late GL treatment; strategy III injection was from days 15
The results revealed that high-mobility group box 1 (HMGB1) protein signal co-localized with the nuclei of some GFAP+ astrocytes (Figure 5A, top panels) and Iba1+ microglia (Figure 5B, top panels) in the ventral column of the spinal cord of naive mice

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the central nervous system (CNS) [1]. Experimental autoimmune encephalomyelitis (EAE) is a mouse model for improving understanding and treatment of MS [2]. Several medications, such as alemtuzumab, rituximab, and fingolimod, have been used to GL Protects EAE prevent MS relapses [3], therapies for acute MS exacerbations are still limited. The released HMGB1 targets its receptor, advanced glycation end product (RAGE), or a toll-like receptor (TLR) such as TLR2/4, and induces the expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, as well as leukocyte adhesion molecules and chemokines [12]

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