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

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2018 Jul 18

PMID 30013568

Citations 30

Authors

Yan Sun

Huoying Chen

Jiapei Dai

Zhongjun Wan

Ping Xiong

Yong Xu

Zhengrong Han

Weitai Chai

Feili Gong

Fang Zheng

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Interleukin-33 Knockout Promotes High Mobility Group Box 1 Release from Astrocytes by Acetylation Mediated by P300/CBP-Associated Factor in Experimental Autoimmune Encephalomyelitis.

Xiao Y, Hao L, Cao X, Zhang Y, Xu Q, Qin L Neurosci Bull. 2025; .

PMID: 40063200 DOI: 10.1007/s12264-025-01374-8.

Pathophysiological role of high mobility group box-1 signaling in neurodegenerative diseases.

Kumar V, Kumar P Inflammopharmacology. 2024; 33(2):703-727.

PMID: 39546221 DOI: 10.1007/s10787-024-01595-9.

Reporting quality and risk of bias of randomized controlled trials of Chinese herbal medicine for multiple sclerosis.

Wu J, Yang J, Hu J, Xu S, Zhang X, Qian S Front Immunol. 2024; 15:1429895.

PMID: 39229262 PMC: 11369894. DOI: 10.3389/fimmu.2024.1429895.

The chemical composition of Diwu YangGan capsule and its potential inhibitory roles on hepatocellular carcinoma by microarray-based transcriptomics.

Shi Q, He J, Chen G, Xu J, Zeng Z, Zhao X J Tradit Complement Med. 2024; 14(4):381-390.

PMID: 39035694 PMC: 11259662. DOI: 10.1016/j.jtcme.2023.12.002.

Microglia at the blood brain barrier in health and disease.

Mayer M, Fischer T Front Cell Neurosci. 2024; 18():1360195.

PMID: 38550920 PMC: 10976855. DOI: 10.3389/fncel.2024.1360195.

References

Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A . Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003; 22(20):5551-60. PMC: 213771. DOI: 10.1093/emboj/cdg516. View

Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S . IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006; 177(1):566-73. DOI: 10.4049/jimmunol.177.1.566. View

Andersson A, Covacu R, Sunnemark D, Danilov A, Dal Bianco A, Khademi M . Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol. 2008; 84(5):1248-55. DOI: 10.1189/jlb.1207844. View

Hwang J, Choi H, Ham S, Yoo T, Lee W, Paek K . Deacetylation-mediated interaction of SIRT1-HMGB1 improves survival in a mouse model of endotoxemia. Sci Rep. 2015; 5:15971. PMC: 4629154. DOI: 10.1038/srep15971. View

Kigerl K, Lai W, Wallace L, Yang H, Popovich P . High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation. Brain Behav Immun. 2017; 72:22-33. PMC: 6681463. DOI: 10.1016/j.bbi.2017.11.018. View

Hayakawa K, Arai K, Lo E . Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. Glia. 2010; 58(8):1007-15. PMC: 3814180. DOI: 10.1002/glia.20982. View

Sun Y, Chen H, Dai J, Zou H, Gao M, Wu H . HMGB1 expression patterns during the progression of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2015; 280:29-35. DOI: 10.1016/j.jneuroim.2015.02.005. View

Grigorian A, Araujo L, Naidu N, Place D, Choudhury B, Demetriou M . N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis. J Biol Chem. 2011; 286(46):40133-41. PMC: 3220534. DOI: 10.1074/jbc.M111.277814. View

Sun Q, Wu W, Hu Y, Li H, Zhang D, Li S . Early release of high-mobility group box 1 (HMGB1) from neurons in experimental subarachnoid hemorrhage in vivo and in vitro. J Neuroinflammation. 2014; 11:106. PMC: 4107626. DOI: 10.1186/1742-2094-11-106. View

10.

Shi Y, Zhang L, Teng J, Miao W . HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol Med Rep. 2018; 17(4):5125-5131. PMC: 5865977. DOI: 10.3892/mmr.2018.8485. View

11.

Uzawa A, Mori M, Taniguchi J, Masuda S, Muto M, Kuwabara S . Anti-high mobility group box 1 monoclonal antibody ameliorates experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2013; 172(1):37-43. PMC: 3719929. DOI: 10.1111/cei.12036. View

12.

Qiu J, Nishimura M, Wang Y, Sims J, Qiu S, Savitz S . Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab. 2007; 28(5):927-38. DOI: 10.1038/sj.jcbfm.9600582. View

13.

Santoro M, Maetzler W, Stathakos P, Martin H, Hobert M, Rattay T . In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin. Neurobiol Dis. 2016; 91:59-68. PMC: 4867789. DOI: 10.1016/j.nbd.2016.02.018. View

14.

Okuma Y, Liu K, Wake H, Liu R, Nishimura Y, Hui Z . Glycyrrhizin inhibits traumatic brain injury by reducing HMGB1-RAGE interaction. Neuropharmacology. 2014; 85:18-26. DOI: 10.1016/j.neuropharm.2014.05.007. View

15.

Weber M, Prodhomme T, Youssef S, Dunn S, Steinman L, Zamvil S . Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation. 2014; 11:29. PMC: 3922392. DOI: 10.1186/1742-2094-11-29. View

16.

Kim S, Jin Y, Shin J, Kim I, Lee H, Park S . Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion. Neurobiol Dis. 2012; 46(1):147-56. DOI: 10.1016/j.nbd.2011.12.056. View

17.

Chen H, Sun Y, Lai L, Wu H, Xiao Y, Ming B . Interleukin-33 is released in spinal cord and suppresses experimental autoimmune encephalomyelitis in mice. Neuroscience. 2015; 308:157-68. DOI: 10.1016/j.neuroscience.2015.09.019. View

18.

Zhang J, Wu Y, Weng Z, Zhou T, Feng T, Lin Y . Glycyrrhizin protects brain against ischemia-reperfusion injury in mice through HMGB1-TLR4-IL-17A signaling pathway. Brain Res. 2014; 1582:176-86. DOI: 10.1016/j.brainres.2014.07.002. View

19.

McGeachy M, Anderton S . Cytokines in the induction and resolution of experimental autoimmune encephalomyelitis. Cytokine. 2005; 32(2):81-4. DOI: 10.1016/j.cyto.2005.07.012. View

20.

Lotze M, Tracey K . High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005; 5(4):331-42. DOI: 10.1038/nri1594. View