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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Research

Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways

Authors: Yi Xie, Xuejiao Chen, Ying Li, Simiao Chen, Shuai Liu, Zhiyuan Yu, Wei Wang

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-β1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-β1 on demyelinating diseases and its underlying mechanisms have not been well investigated.

Methods

A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-β1 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism.

Results

The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-β1. Besides, TGF-β1 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1β, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-β1. Mechanistically, TGF-β1 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1β. Activation of ERK1/2 and NF-κB pathways largely abolished the protective effects of TGF-β1, which indicated that TGF-β1 alleviated the pyroptosis possibly via regulating NF-κB/ERK1/2 signal pathways.

Conclusions

Our studies demonstrated TGF-β1 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1/2 and NF-κB pathways. Targeting TGF-β1 activity might serve as a promising therapeutic strategy in demyelinating diseases.
Appendix
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Metadata
Title
Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways
Authors
Yi Xie
Xuejiao Chen
Ying Li
Simiao Chen
Shuai Liu
Zhiyuan Yu
Wei Wang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02557-0

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