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

Overview

Journal Front Pharmacol

Date 2020 Oct 5

PMID 33013394

Citations 8

Authors

Minju Kim

Soyoung Lee

Hyungjin Lim

Jihye Lee

Ji-Young Park

Hyung-Jun Kwon

In-Chul Lee

Young-Bae Ryu

Jeongtae Kim

Taekyun Shin

Ginnae Ahn

Mun-Chual Rho

Kyungsook Jung

Affiliations

Soon will be listed here.

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) 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.

Citing Articles

Principal Bioactive Properties of Oleanolic Acid, Its Derivatives, and Analogues.

Jannus F, Sainz J, Reyes-Zurita F Molecules. 2024; 29(14).

PMID: 39064870 PMC: 11279785. DOI: 10.3390/molecules29143291.

Eugenol ameliorates uveitis in mice with experimental autoimmune encephalomyelitis through the suppression of key inflammatory genes.

Hong S, Jung K, Ahn M, Kim J, Moon C, Shin T Anim Cells Syst (Seoul). 2024; 28(1):37-44.

PMID: 38249123 PMC: 10798281. DOI: 10.1080/19768354.2024.2304557.

Neuroprotective effects of crude extracts, compounds, and isolated molecules obtained from plants in the central nervous system injuries: a systematic review.

Moura M, Mesquita da Conceicao Bahia G, Goncalves Correa M, Araujo Sarges M, Lobao T, Sanches E Front Neurosci. 2023; 17:1249685.

PMID: 37766783 PMC: 10520969. DOI: 10.3389/fnins.2023.1249685.

Analysis of Differential TLR Activation in a Mouse Model of Multiple Sclerosis.

Suvieri C, Volpi C Methods Mol Biol. 2023; 2700:229-247.

PMID: 37603185 DOI: 10.1007/978-1-0716-3366-3_14.

Immunomodulatory properties of triterpenes.

Renda G, Gokkaya I, Sohretoglu D Phytochem Rev. 2021; 21(2):537-563.

PMID: 34812259 PMC: 8600492. DOI: 10.1007/s11101-021-09785-x.

References

Lim H, Jang H, Kim M, Lee S, Lee S, Lee S . Oleanolic Acid Acetate Exerts Anti-Inflammatory Activity via IKKα/β Suppression in TLR3-Mediated NF-κB Activation. Molecules. 2019; 24(21). PMC: 6866124. DOI: 10.3390/molecules24214002. View

Borjini N, Fernandez M, Giardino L, Calza L . Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis. J Neuroinflammation. 2016; 13(1):291. PMC: 5111339. DOI: 10.1186/s12974-016-0757-6. View

Jones M, Nguyen T, Deboy C, Griffin J, Whartenby K, Kerr D . Behavioral and pathological outcomes in MOG 35-55 experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008; 199(1-2):83-93. DOI: 10.1016/j.jneuroim.2008.05.013. View

Deerhake M, Biswas D, Barclay W, Shinohara M . Pattern Recognition Receptors in Multiple Sclerosis and Its Animal Models. Front Immunol. 2019; 10:2644. PMC: 6861384. DOI: 10.3389/fimmu.2019.02644. View

Hasheminia S, Zarkesh-Esfahani S, Tolouei S, Shaygannejad V, Shirzad H, Hashemzadeh Chaleshtory M . Toll like receptor 2 and 4 expression in peripheral blood mononuclear cells of multiple sclerosis patients. Iran J Immunol. 2014; 11(2):74-83. DOI: IJIv11i2A2. View

Leibowitz S, Yan J . NF-κB Pathways in the Pathogenesis of Multiple Sclerosis and the Therapeutic Implications. Front Mol Neurosci. 2016; 9:84. PMC: 5023675. DOI: 10.3389/fnmol.2016.00084. View

Kumar V . Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol. 2019; 332:16-30. DOI: 10.1016/j.jneuroim.2019.03.012. View

Vijay K . Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol. 2018; 59:391-412. PMC: 7106078. DOI: 10.1016/j.intimp.2018.03.002. View

Hwang-Bo J, Bae M, Park J, Chung I . 3-O-Acetyloleanolic acid inhibits VEGF-A-induced lymphangiogenesis and lymph node metastasis in an oral cancer sentinel lymph node animal model. BMC Cancer. 2018; 18(1):714. PMC: 6034267. DOI: 10.1186/s12885-018-4630-0. View

10.

Palle P, Monaghan K, Milne S, Wan E . Cytokine Signaling in Multiple Sclerosis and Its Therapeutic Applications. Med Sci (Basel). 2017; 5(4). PMC: 5753652. DOI: 10.3390/medsci5040023. View

11.

Hoffmann O, Braun J, Becker D, Halle A, Freyer D, Dagand E . TLR2 mediates neuroinflammation and neuronal damage. J Immunol. 2007; 178(10):6476-81. DOI: 10.4049/jimmunol.178.10.6476. View

12.

Kim H, Walczak P, Muja N, Campanelli J, Bulte J . ICV-transplanted human glial precursor cells are short-lived yet exert immunomodulatory effects in mice with EAE. Glia. 2012; 60(7):1117-29. PMC: 3579214. DOI: 10.1002/glia.22339. View

13.

Kawai T, Akira S . Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007; 13(11):460-9. DOI: 10.1016/j.molmed.2007.09.002. View

14.

Hilliard B, Samoilova E, Liu T, Rostami A, Chen Y . Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J Immunol. 1999; 163(5):2937-43. View

15.

Verstak B, Nagpal K, Bottomley S, Golenbock D, Hertzog P, Mansell A . MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. J Biol Chem. 2009; 284(36):24192-203. PMC: 2782013. DOI: 10.1074/jbc.M109.023044. View

16.

Kim J, Cheon Y, Oh H, Rho M, Erkhembaatar M, Kim M . Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2-Ca(2+)-NFATc1 signaling, and suppresses bone loss in mice. Bone. 2013; 60:104-11. DOI: 10.1016/j.bone.2013.12.013. View

17.

Bsibsi M, Ravid R, Gveric D, van Noort J . Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002; 61(11):1013-21. DOI: 10.1093/jnen/61.11.1013. View

18.

Lin H, Tang C, Chen Y, Wei I, Chen J, Lai C . Peptidoglycan enhances proinflammatory cytokine expression through the TLR2 receptor, MyD88, phosphatidylinositol 3-kinase/AKT and NF-kappaB pathways in BV-2 microglia. Int Immunopharmacol. 2010; 10(8):883-91. DOI: 10.1016/j.intimp.2010.04.026. View

19.

Shi G, Vistica B, Nugent L, Tan C, Wawrousek E, Klinman D . Differential involvement of Th1 and Th17 in pathogenic autoimmune processes triggered by different TLR ligands. J Immunol. 2013; 191(1):415-23. PMC: 3749791. DOI: 10.4049/jimmunol.1201732. View

20.

Ouyang S, Hsuchou H, Kastin A, Mishra P, Wang Y, Pan W . Leukocyte infiltration into spinal cord of EAE mice is attenuated by removal of endothelial leptin signaling. Brain Behav Immun. 2014; 40:61-73. PMC: 4131983. DOI: 10.1016/j.bbi.2014.02.003. View