Highlights
- •We investigated the possible immunomodulatory effects of S3I-201.
- •S3I-201 attenuates clinical symptoms of EAE mice.
- •S3I-201 downregulates Th1/Th17 signaling in EAE mice.
- •S3I-201 upregulates treg transcription factor signaling.
- •S3I-201 could be used as a novel candidate for MS treatment.
Abstract
CD4+ T cells, specifically Th cells (Th1 and Th17) and regulatory T cells (Tregs), play
a pivotal role in the pathogenesis of multiple sclerosis (MS), a demyelinating autoimmune
disease of the CNS. STAT3 inhibitors are potential therapeutic targets for several
immune disorders. In this study, we investigated the role of a well-known STAT3 inhibitor,
S3I-201, in experimental autoimmune encephalomyelitis (EAE), a model of MS. Following
induction of EAE, mice were intraperitoneally administered S3I-201 (10 mg/kg) each
day, beginning on day 14 and continuing till day 35 and were evaluated for clinical
signs. Flow cytometry was used to investigate further the effect of S3I-201 on Th1
(IFN-γ, STAT1, pSTAT1, and T-bet), Th17 (IL-17A, STAT3, pSTAT3, and RORγt), and regulatory
T cells (Treg, IL-10, TGF-β1, and FoxP3) expressed in splenic CD4+ T cells. Moreover, we analyzed the effects of S3I-201 on mRNA and protein expression
of IFN-γ, T-bet, IL-17A, STAT1, STAT3, pSTAT1, pSTAT3, RORγ, IL-10, TGF-β1, and FoxP3
in the brains of EAE mice. The severity of clinical scores decreased in S3I-201-treated
EAE mice compared to vehicle-treated EAE mice. S3I-201 treatment significantly decreased
CD4+IFN-γ+, CD4+STAT1+, CD4+pSTAT1+, CD4+T-bet+, CD4+IL-17A+, CD4+STAT3+, CD4+pSTAT3+, and CD4+RORγt+ and increased CD4+IL-10+, CD4+TGF-β1+, and CD4+FoxP3+ in the spleens of EAE mice. Additionally, S3I-201 administration in EAE mice significantly
decreased the mRNA and protein expression of Th1 and Th17 and increased those of Treg.
These results suggest that S3I-201 may have novel therapeutic potential against MS.
Keywords
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Article info
Publication history
Published online: March 22, 2023
Accepted:
March 21,
2023
Received in revised form:
March 13,
2023
Received:
January 27,
2023
Identification
Copyright
© 2023 Elsevier B.V. All rights reserved.
