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Inflammation Research
Published in: Inflammation Research 4/2019

01-04-2019 | Multiple Sclerosis | Original Research Paper

Celastrol suppresses experimental autoimmune encephalomyelitis via MAPK/SGK1-regulated mediators of autoimmune pathology

Authors: Shivaprasad H. Venkatesha, Kamal D. Moudgil

Published in: Inflammation Research | Issue 4/2019

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Abstract

Objective and design

Multiple sclerosis (MS) is a debilitating autoimmune disease involving immune dysregulation of the pathogenic T helper 17 (Th17) versus protective T regulatory (Treg) cell subsets, besides other cellular aberrations. Studies on the mechanisms underlying these changes have unraveled the involvement of mitogen-activated protein kinase (MAPK) pathway in the disease process. We describe here a gene expression- and bioinformatics-based study showing that celastrol, a natural triterpenoid, acting via MAPK pathway regulates the downstream genes encoding serum/glucocorticoid regulated kinase 1 (SGK1), which plays a vital role in Th17/Treg differentiation, and brain-derived neurotrophic factor (BDNF), which is a neurotrophic factor, thereby offering protection against experimental autoimmune encephalomyelitis (EAE) in mice.

Methods

We first tested the gene expression profile of splenocytes of EAE mice in response to the disease-related antigen, myelin oligodendrocyte glycoprotein (MOG), and then examined the effect of celastrol on that profile.

Results

Interestingly, celastrol reversed the expression of many MOG-induced genes involved in inflammation and immune pathology. The MAPK pathway involving p38MAPK and ERK was identified as one of the mediators of celastrol action. It involved suppression of SGK1 but upregulation of BDNF, which then contributed to protection against EAE.

Conclusion

Our results not only provide novel insights into disease pathogenesis, but also offer promising therapeutic targets for MS.
Appendix
Available only for authorised users
Literature
1.
Bhise V, Dhib-Jalbut S. Further understanding of the immunopathology of multiple sclerosis: impact on future treatments. Expert Rev Clin Immunol. 2016;12(10):1069–89.CrossRefPubMed
2.
Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011;17(Suppl 5 Improving):139–45.
3.
Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology. 2016;86(11):1014–21.CrossRefPubMedPubMedCentral
4.
Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol. 2015;28(3):206–19.CrossRefPubMed
5.
6.
Holmoy T. The immunology of multiple sclerosis: disease mechanisms and therapeutic targets. Minerva Med. 2008;99(2):119–40.PubMed
7.
Zozulya AL, Wiendl H. The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol. 2008;4(7):384–98.CrossRefPubMed
8.
Di Mitri D, Sambucci M, Loiarro M, De Bardi M, Volpe E, Cencioni MT, Gasperini C, Centonze D, Sette C, Akbar AN, et al. The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis. Immunology. 2015;146(2):251–63.CrossRefPubMedPubMedCentral
9.
Lochner M, Wang Z, Sparwasser T. The special relationship in the development and function of T helper 17 and regulatory T cells. Prog Mol Biol Transl Sci. 2015;136:99–129.CrossRefPubMed
10.
Wang C, Collins M, Kuchroo VK. Effector T cell differentiation: are master regulators of effector T cells still the masters? Curr Opin Immunol. 2015;37:6–10.CrossRefPubMed
11.
Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med. 2009;361(9):888–98.CrossRefPubMed
12.
Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Ann Rev Immunol. 2009;27:485–517.CrossRef
13.
14.
Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Ann Rev Immunol. 2012;30:531–64.CrossRef
15.
Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules 2017;22(1):134.CrossRefPubMedCentral
16.
Fessler J, Felber A, Duftner C, Dejaco C. Therapeutic potential of regulatory T cells in autoimmune disorders. BioDrugs. 2013;27(4):281–91.CrossRefPubMed
17.
Mai J, Wang H, Yang XF. Th 17 cells interplay with Foxp3+ Tregs in regulation of inflammation and autoimmunity. Front Biosci (Landmark Ed). 2010;15:986–1006.CrossRef
18.
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518–22.CrossRefPubMedPubMedCentral
19.
Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013;496(7446):513–7.CrossRefPubMedPubMedCentral
20.
Krementsov DN, Thornton TM, Teuscher C, Rincon M. The emerging role of p38 mitogenactivated protein kinase in multiple sclerosis and its models. Mol Cell Biol. 2013;33(19):3728–34.CrossRefPubMedPubMedCentral
21.
Canto E, Isobe N, Didonna A, Hauser SL, Oksenberg JR. Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients. J Neuroinflammation. 2018;15(1):72.CrossRefPubMedPubMedCentral
22.
Huang G, Wang Y, Vogel P, Chi H. Control of IL-17 receptor signaling and tissue inflammation by the p38alpha-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal. 2015;8(366):ra24.CrossRefPubMedPubMedCentral
23.
Krementsov DN, Noubade R, Dragon JA, Otsu K, Rincon M, Teuscher C. Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol. 2014;75(1):50–66.CrossRefPubMedPubMedCentral
24.
Namiki K, Matsunaga H, Yoshioka K, Tanaka K, Murata K, Ishida J, Sakairi A, Kim J, Tokuhara N, Shibakawa N, et al. Mechanism for p38alpha-mediated experimental autoimmune encephalomyelitis. J Biol Chem. 2012;287(29):24228–38.CrossRefPubMedPubMedCentral
25.
Noubade R, Krementsov DN, Del Rio R, Thornton T, Nagaleekar V, Saligrama N, Spitzack A, Spach K, Sabio G, Davis RJ, et al. Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis. Blood. 2011;118(12):3290–300.CrossRefPubMedPubMedCentral
26.
Wang L, Li B, Quan MY, Li L, Chen Y, Tan GJ, Zhang J, Liu XP, Guo L. Mechanism of oxidative stress p38MAPK-SGK1 signaling axis in experimental autoimmune encephalomyelitis (EAE). Oncotarget. 2017;8(26):42808–16.PubMedPubMedCentral
27.
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochimica et biophysica acta. 2010;1802(4):396–405.CrossRefPubMed
28.
Astry B, Venkatesha SH, Laurence A, Christensen-Quick A, Garzino-Demo A, Frieman MB, O’Shea JJ, Moudgil KD. Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ. Clin Immunol. 2015;157(2):228–38.CrossRefPubMedPubMedCentral
29.
Nanjundaiah SM, Venkatesha SH, Yu H, Tong L, Stains JP, Moudgil KD. Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J Biol Chem. 2012;287(26):22216–26.CrossRefPubMedPubMedCentral
30.
Venkatesha SH, Dudics S, Astry B, Moudgil KD. Control of autoimmune inflammation by celastrol, a natural triterpenoid. Pathogens Dis 2016;74(6):ftw059.CrossRef
31.
Venkatesha SH, Yu H, Rajaiah R, Tong L, Moudgil KD. Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. J Biol Chem. 2011;286(17):15138–46.CrossRefPubMedPubMedCentral
32.
Abdin AA, Hasby EA. Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3 + T-lymphocyte expression in a relapsing-remitting model of multiple sclerosis in rats. Eur J Pharmacol. 2014;742:102–12.CrossRefPubMed
33.
Wang Y, Cao L, Xu LM, Cao FF, Peng B, Zhang X, Shen YF, Uzan G, Zhang DH. Celastrol ameliorates EAE induction by suppressing pathogenic T cell responses in the peripheral and central nervous systems. J Neuroimmune Pharmacol. 2015;10(3):506–16.CrossRefPubMed
34.
Yang H, Liu C, Jiang J, Wang Y, Zhang X. Celastrol attenuates multiple sclerosis and optic neuritis in an experimental autoimmune encephalomyelitis model. Front Pharmacol. 2017;8:44.PubMedPubMedCentral
35.
Bittner S, Afzali AM, Wiendl H, Meuth SG. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. J Vis Exp. 2014;86:e51275.
36.
Kwong B, Rua R, Gao Y, Flickinger J Jr, Wang Y, Kruhlak MJ, Zhu J, Vivier E, McGavern DB, Lazarevic V. T-bet-dependent NKp46(+) innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. Nat Immunol. 2017;18(10):1117–27.CrossRefPubMedPubMedCentral
37.
Wu C, Chen Z, Xiao S, Thalhamer T, Madi A, Han T, Kuchroo V. SGK1 governs the reciprocal development of Th17 and regulatory T cells. Cell Rep. 2018;22(3):653–65.CrossRefPubMedPubMedCentral
38.
39.
40.
Venkatesha SH, Moudgil KD. Celastrol and its role in controlling chronic diseases. Adv Exp Med Biol. 2016;928:267–89.CrossRefPubMed
41.
Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011;303(1):9–20.CrossRefPubMed
42.
Salminen A, Lehtonen M, Paimela T, Kaarniranta K. Celastrol: molecular targets of thunder god vine. Biochem Biophys Res Commun. 2010;394(3):439–42.CrossRefPubMed
43.
Faust K, Gehrke S, Yang Y, Yang L, Beal MF, Lu B. Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson’s disease. BMC Neurosci. 2009;10:109.CrossRefPubMedPubMedCentral
44.
Gu L, Bai W, Li S, Zhang Y, Han Y, Gu Y, Meng G, Xie L, Wang J, Xiao Y, et al. Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress. PLoS One. 2013;8(6):e65477.CrossRefPubMedPubMedCentral
45.
Cascao R, Fonseca JE, Moita LF. Celastrol: a spectrum of treatment opportunities in chronic diseases. Front Med (Lausanne). 2017;4:69.CrossRef
46.
Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010;29(3):405–34.CrossRefPubMedPubMedCentral
47.
Choi BS, Kim H, Lee HJ, Sapkota K, Park SE, Kim S, Kim SJ. Celastrol from ‘Thunder God Vine’ protects SH-SY5Y cells through the preservation of mitochondrial function and inhibition of p38 MAPK in a rotenone model of Parkinson’s disease. Neurochem Res. 2014;39(1):84–96.CrossRefPubMed
48.
Luo D, Guo Y, Cheng Y, Zhao J, Wang Y, Rong J. Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2/HO-1, MAP kinase and NF-kappaB pathways. Aging (Albany NY). 2017;9(10):2069–82.CrossRef
49.
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J Clin Invest. 2015;125(11):4212–22.CrossRefPubMedPubMedCentral
50.
van der Meer JW, Netea MG. A salty taste to autoimmunity. The New England journal of medicine. 2013;368(26):2520–1.CrossRefPubMed
51.
BelAiba RS, Djordjevic T, Bonello S, Artunc F, Lang F, Hess J, Gorlach A. The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. Circ Res. 2006;98(6):828–36.CrossRefPubMed
52.
Pastore D, Della-Morte D, Coppola A, Capuani B, Lombardo MF, Pacifici F, Ferrelli F, Arriga R, Mammi C, Federici M, et al. SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-alpha. Cell Death Dis. 2015;6:e1890.CrossRefPubMedPubMedCentral
53.
Bell LM, Leong ML, Kim B, Wang E, Park J, Hemmings BA, Firestone GL. Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPK-dependent pathway. J Biol Chem. 2000;275(33):25262–72.CrossRefPubMed
54.
De Santi L, Annunziata P, Sessa E, Bramanti P. Brain-derived neurotrophic factor and TrkB receptor in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neurol Sci. 2009;287(1–2):17–26.CrossRefPubMed
55.
Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125(Pt 1):75–85.CrossRefPubMed
56.
Linker R, Gold R, Luhder F. Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol. 2009;29(1):43–68.CrossRefPubMed
57.
Smith PA, Schmid C, Zurbruegg S, Jivkov M, Doelemeyer A, Theil D, Dubost V, Beckmann N. Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis. J Neuroimmunol. 2018;318:103–13.CrossRefPubMed
58.
Murphy AC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010;24(4):641–51.CrossRefPubMed
59.
Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med. 2008;14(3):337–42.CrossRefPubMedPubMedCentral
60.
Veerappan K, Natarajan S, Ethiraj P, Vetrivel U, Samuel S. Inhibition of IKKbeta by celastrol and its analogues - an in silico and in vitro approach. Pharm Biol. 2017;55(1):368–73.CrossRefPubMed
61.
Qiu X, Luo H, Liu X, Guo Q, Zheng K. Fan D1, Shen J. Lu C1, He X, Zhang G, Lu A. Therapeutic Potential of Pien Tze Huang on Experimental AutoimmuneEncephalomyelitis Rat. J Immunol Res. 2018;2018:2952471CrossRefPubMedPubMedCentral
62.
Yang L, Xing F, Han X, Li Q, Wu H, Shi H, Wang Z, Huang F, Wu X. Astragaloside IV regulates differentiation and induces apoptosis of activated CD4+ T cells in the pathogenesis of experimental autoimmune encephalomyelitis. Toxicol Appl Pharmacol. 2018;362:105–115.CrossRefPubMed
Metadata
Title
Celastrol suppresses experimental autoimmune encephalomyelitis via MAPK/SGK1-regulated mediators of autoimmune pathology
Authors
Shivaprasad H. Venkatesha
Kamal D. Moudgil
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 4/2019
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-019-01219-x

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