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Resveratrol (3, 5, 4′-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain

  • K. Alexa Orr Gandy
  • Jiajia Zhang
  • Prakash Nagarkatti
  • Mitzi NagarkattiEmail author
ORIGINAL ARTICLE

Abstract

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) (RES) is a naturally-derived phytoestrogen found in the skins of red grapes and berries and has potential as a novel and effective therapeutic agent. In the current study, we investigated the role of microRNA (miRNA) in RES-mediated attenuation of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Administration of RES effectively decreased disease severity, including inflammation and central nervous system immune cell infiltration. miRNA microarray analysis revealed an altered miRNA profile in encephalitogenic CD4+ T cells from EAE mice exposed to RES treatment. Additionally, bioinformatics and in silico pathway analysis suggested the involvement of RES-induced miRNA in pathways and processes that regulated cellular proliferation. Additional studies confirmed that RES affected cell cycle progression and apoptosis in activated T cells, specifically in the brain. RES treatment significantly upregulated miR-124 during EAE, while suppressing associated target gene, sphingosine kinase 1 (SK1), and this too was specific to mononuclear cells in the brains of treated mice, as peripheral immune cells remained unaltered upon RES treatment. Collectively, these studies demonstrate that RES treatment leads to amelioration of EAE development through mechanism(s) potentially involving suppression of neuroinflammation via alteration of the miR-124/SK1 axis, thereby halting cell-cycle progression and promoting apoptosis in activated encephalitogenic T cells.

Graphical Abstract

Resveratrol alters the miR-124/sphingosine kinase 1 (SK1) axis in encephalitogenic T cells, promotes cell-cycle arrest and apoptosis, and decreases neuroinflammation in experiemental autoimmune encephalomyelitis (EAE).

Keywords

Experimental autoimmune encephalitis (EAE) Resveratrol (RES) CD4+ T cells microRNA 124 (miR-124) Sphingosine kinase 1 (SK1) Multiple sclerosis (MS) 

Notes

Acknowledgments

The studies were supported in part by NIH grants F32AT008539, P01AT003961, R01AT006888, R01AI123947, R01AI129788, R01MH094755, and P20GM103641.

Author Contributions

A.O.G. planned and carried out all experiments and analyses, wrote the manuscript and prepared all figures.

J.Z. performed statistical analyses when R program was employed. P.N. and M.N. supervised all work presented in this manuscript. All authors (A.O.G., J.Z., P.N., and M.N.) reviewed this manuscript.

Compliance with Ethical Standards

Competing Interests

The authors declare no financial or non-financial competing interests.

Supplementary material

11481_2019_9842_MOESM1_ESM.jpg (35 kb)
Supplemental Figure 1 Validation of microarray top up-regulated miRNAs. Brain-derived CD4+ T cells were isolated and the top five up-regulated miRNAs detected by microarray analysis were validated: miR-124, miR-132, miR-128, miR-138 and miR-127. Statistical significance was assessed using a two-tailed Student’s t test, *, *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. n > 4 independent experiments. (JPG 35 kb)
11481_2019_9842_MOESM2_ESM.jpg (185 kb)
Supplemental Figure 2 Schematic representation of miR-124/SK1 axis in cell-cycle arrest and apoptosis. miR-124 targets SK1, preventing the production of sphingosine-1 phosphate (S1P), thus, inhibiting pro-survival and proliferative functions of S1P. Furthermore, inhibition of SK1 results in metabolic flux, leading to increased sphingosine and ceramide levels, which drive cell-cycle arrest and apoptosis. Figure adapted from (Hannun and Obeid 2008). SMase, sphingomeylinse; CDase, ceramidase; SK1, sphingosine kinase 1 (JPG 185 kb)
11481_2019_9842_MOESM3_ESM.jpg (48 kb)
Supplemental Figure 3 In vitro Resveratrol treatment does not affect miR-124 expression. Splenocytes or lymphocytes (derived from inguinal lymph nodes) were isolated from naïve or EAE + VEH mice and treated for 48 h with 2.5μg/mL Concanavalin A (ConA) or 72 h with 30μg/mL MOG. CD4+ cells were isolated and miR-124 expression was evaluated by qRT-PCR. Scale is used to enable comparison of in vitro stimulated miR-124 expression with encephalitogenic CD4+ T cells (Fig. 6a). MNE, mean normalized expression. (JPG 47 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • K. Alexa Orr Gandy
    • 1
  • Jiajia Zhang
    • 2
  • Prakash Nagarkatti
    • 1
  • Mitzi Nagarkatti
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Pathology, Microbiology and Immunology, School of MedicineUniversity of South CarolinaColumbiaUSA
  2. 2.Epidemiology and Biostatistics, Arnold School of Public HealthUniversity of South CarolinaColumbiaUSA
  3. 3.WJB Dorn VA Medical CenterColumbiaUSA

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