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Cited by 36Multiple Sclerosis Research StudiesNatural Compounds in Disease TreatmentT-cell and B-cell Immunology

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

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Venkatesha, Shivaprasad H., Moudgil, Kamal D.·2019·Inflammation Research
DOI 10.1007/s00011-019-01219-xPMC PMC6517245
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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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  • Inhibiting SGK1 expression can induce BDNF expression in T cells under Th17 differentiating conditions.

    “Interestingly, inhibiting the expression of SGK1 can induce the expression of Brain-Derived Neurotrophic Factor (BDNF) in T cells under Th17 differentiating conditions”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Venkatesha and Moudgil, 2019

    The Results section (Fig. 4B; page unavailable) reports that celastrol lowered SGK1 expression and raised BDNF expression in T cells cultured under Th17-differentiation conditions. It does not show that inhibiting SGK1 itself induced BDNF: the Results section on MAPK (Fig. 5; page unavailable) identifies p38 MAPK as an upstream regulator of both genes. (LLM, conf=0.87)

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Authors
Venkatesha, S. H., & Moudgil, K. D.
Affiliations
University of Maryland, Baltimore (US)
Corresponding author
Moudgil, Kamal D.
ORCID
Moudgil, Kamal D.
Venue
Inflammation Research
Publisher
Springer Science and Business Media LLC
Published
2019-02-28
Volume
68
Issue
4
Pages
285-296
ISSN
  • 1023-3830 (ISSN-L)
  • 1420-908X
DOI
10.1007/s00011-019-01219-x
PMC
PMC6517245
OpenAlex
W2915212160
Cited by
36
References
3
Citations by year
2026: 2 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 9 · 2021: 5 · 2020: 2 · 2019: 2
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Inflammation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health, Bethesda, USA (1R21NS082918, R01 AT 004321)
  • U.S. Department of Veterans Affairs (I01 BX002424)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
celastrol, experimental autoimmune encephalomyelitis, multiple sclerosis, MAPK signaling, SGK1, brain-derived neurotrophic factor, Th17/Treg balance, myelin oligodendrocyte glycoprotein, p38 MAPK, ERK, triterpenoids, neuroprotection, immunomodulation
MeSH terms
Serum-Glucocorticoid Regulated Kinases, Animals, Anti-Inflammatory Agents, Encephalomyelitis, Autoimmune, Experimental, Gene Expression Regulation, Immunologic Factors, Male, Mice, Inbred C57BL, Spleen, T-Lymphocytes, Triterpenes, Cytokines, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Brain-Derived Neurotrophic Factor, Mitogen-Activated Protein Kinases, Pentacyclic Triterpenes, Myelin-Oligodendrocyte Glycoprotein

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