Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. It is characterized by impaired social communication, abnormal social interactions, and repetitive behaviors and/or restricted interests. BTBR T + tf/J (BTBR) inbred mice are commonly used as a model for ASD. Resveratrol is used widely as a beneficial therapeutic in the treatment of an extensive array of pathologies, including neurodegenerative diseases. In the present study, the effect of resveratrol administration (20 and 40 mg/kg) was evaluated in both BTBR and C57BL/6 (B6) mice. Behavioral (self-grooming), Foxp3, T-bet, GATA-3, RORγt, and IL-17A in CD4+ T cells were assessed. Our study showed that BTBR control mice exhibited a distinct immune profile from that of the B6 control mice. BTBR mice were characterized by lower levels of Foxp3+ and higher levels of RORγt+, T-bet+, and GATA-3+ production in CD4+ T cells when compared with B6 control. Resveratrol (20 and 40 mg/kg) treatment to B6 and BTBR mice showed substantial induction of Foxp3+ and reduction of T-bet+, GATA-3+, and IL-17A+ expression in CD4+ cells when compared with the respective control groups. Moreover, resveratrol treatment resulted in upregulated expression of Foxp3 mRNA and decreased expression levels of T-bet, GATA-3, RORγt, and IL-17A in the spleen and brain tissues. Western blot analysis confirmed that resveratrol treatment decreased the protein expression of T-bet, GATA-3, RORγ, and IL-17 and that it increased Foxp3 in B6 and BTBR mice. Our results suggest that autism is associated with dysregulation of transcription factor signaling that can be corrected by resveratrol treatment.

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Abbreviations

ASD:

Autism spectrum disorder

CD4:

Cluster of differentiation 4

Th cells:

T helper cells

IL:

Interleukin

Foxp3:

Forkhead box P3

STAT3:

Signal transducer and activator of transcription 3

RORγt:

retinoid-acid receptor-related orphan receptor gamma t

T-bet:

T-box transcription factor

GATA3:

GATA binding protein 3

mRNA:

Messenger RNA

RT-PCR:

Reverse transcription polymerase chain reaction

FITC:

Fluoroisothiocyanate

PE:

Phycoerythrin

i.p:

Intraperitoneally

DMSO:

Dimethyl sulfoxide

CNS:

Central nervous system

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Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-120.

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Correspondence to Sheikh Fayaz Ahmad.

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All procedures were performed with the approval of the Institutional Animal Care and Use Committee.

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Bakheet, S.A., Alzahrani, M.Z., Ansari, M.A. et al. Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism. Mol Neurobiol 54, 5201–5212 (2017). https://doi.org/10.1007/s12035-016-0066-1

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Keywords

  • Autism
  • Resveratrol
  • BTBR T + tf/J, C57BL/6 J
  • Transcription factors
  • CD4 cells