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Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Research

Regulatory T cells alleviate myelin loss and cognitive dysfunction by regulating neuroinflammation and microglial pyroptosis via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination

Authors: Yao Wang, Dilinuer Sadike, Bo Huang, Ping Li, Qiao Wu, Na Jiang, Yongkang Fang, Guini Song, Li Xu, Wei Wang, Minjie Xie

Published in: Journal of Neuroinflammation | Issue 1/2023

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Abstract

Demyelination occurs in multiple central nervous system (CNS) disorders and is tightly associated with neuroinflammation. Pyroptosis is a form of pro-inflammatory and lytic cell death which has been observed in CNS diseases recently. Regulatory T cells (Tregs) have exhibited immunoregulatory and protective effects in CNS diseases. However, the roles of Tregs in pyroptosis and their involvement in LPC-induced demyelination have not been explicated. In our study, Foxp3-diphtheria toxin receptor (DTR) mice treated with diphtheria toxin (DT) or PBS were subjected to two-site lysophosphatidylcholine (LPC) injection. Immunofluorescence, western blot, Luxol fast blue (LFB) staining, quantitative real-time PCR (qRT-PCR) and neurobehavior assessments were performed to evaluate the severity of demyelination, neuroinflammation and pyroptosis. Pyroptosis inhibitor was further used to investigate the role of pyroptosis in LPC-induced demyelination. RNA-sequencing was applied to explore the potential regulatory mechanism underlying the involvement of Tregs in LPC-induced demyelination and pyroptosis. Our results showed that depletion of Tregs aggravated microgliosis, inflammatory responses, immune cells infiltration and led to exacerbated myelin injury as well as cognitive defects in LPC-induced demyelination. Microglial pyroptosis was observed after LPC-induced demyelination, which was aggravated by Tregs depletion. Inhibition of pyroptosis by VX765 reversed myelin injury and cognitive function exacerbated by Tregs depletion. RNA-sequencing showed TLR4/myeloid differentiation marker 88 (MyD88) as the central molecules in Tregs-pyroptosis pathway, and refraining TLR4/MyD88/NF-κB pathway alleviated the aggravated pyroptosis induced by Tregs depletion. In conclusion, our findings for the first time indicate that Tregs alleviate myelin loss and improve cognitive function by inhibiting pyroptosis in microglia via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination.
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Metadata
Title
Regulatory T cells alleviate myelin loss and cognitive dysfunction by regulating neuroinflammation and microglial pyroptosis via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination
Authors
Yao Wang
Dilinuer Sadike
Bo Huang
Ping Li
Qiao Wu
Na Jiang
Yongkang Fang
Guini Song
Li Xu
Wei Wang
Minjie Xie
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02721-0

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