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

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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.

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Abbreviations

AP-1:

Activator protein 1

BDNF:

Brain-derived neurotrophic factor

CEBPB:

CCAAT enhancer binding protein β1

ERK1/2:

Extracellular signal-regulated kinase ½

GSK3B:

Glycogen synthase kinase 3 beta

IKBKB:

Inhibitor of Nuclear factor kappa B kinase subunit beta

IRF8:

Interferon regulatory factor 8

MAPK:

Mitogen-activated protein kinase

MOG:

Myelin oligodendrocyte glycoprotein

NFKB1:

Nuclear factor kappa B subunit 1

NFKBIA:

NFKB inhibitor alpha

NR3C1:

Nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor

PKC:

Protein kinase C

RELA:

Rel-like domain-containing proteins

SGK1:

Serum/glucocorticoid regulated kinase 1

SP1:

Specificity protein 1

STAT4:

Signal transducer and activator of transcription 4

TLR:

Toll-like receptor

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Acknowledgements

This work was supported in part by Grants (1R21NS082918 and R01 AT 004321) from the National Institutes of Health, Bethesda, MD and in part by VA Merit Review Award # 5 I01 BX002424 (to KDM) from the United States (U.S.) Department of Veterans Affairs [Biomedical Laboratory Research and Development Service]. We thank Jason Lees (USUHS, Bethesda) and Bodhraj Acharya (UMB) for helpful advice and discussion regarding the MOG-EAE model. We thank Rakeshchandra Reddy Meka and Steven Dudics for help with some experiments. We also thank Carol Fowler and Tom Bowen for help with the VA Research Facilities. This material is the result of work supported in part with resources and the use of facilities at the VA Maryland Health Care System, Baltimore, Maryland.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Shivaprasad H. Venkatesha & Kamal D. Moudgil

  2. Baltimore VA Medical Center, Baltimore, MD, 21201, USA

    Shivaprasad H. Venkatesha & Kamal D. Moudgil

  3. Division of Rheumatology, Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite-380, Baltimore, MD, 21201, USA

    Kamal D. Moudgil

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Venkatesha, S.H., Moudgil, K.D. Celastrol suppresses experimental autoimmune encephalomyelitis via MAPK/SGK1-regulated mediators of autoimmune pathology. Inflamm. Res. 68, 285–296 (2019). https://doi.org/10.1007/s00011-019-01219-x

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