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Regulation of Microglial Activation by Wnt/β-Catenin Signaling After Global Cerebral Ischemia in Mice

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Abstract

Microglia are immunocompetent cells in the central nervous system. Following cerebral ischemia, microglia will be rapidly activated and undergo proliferation, morphological transformation, and changes in gene expression and function. At present, the regulatory mechanisms of microglial activation following ischemia remain largely unclear. In this study, we took advantage of CX3CR1GFP/+ fluorescent mice and a global cerebral ischemia-reperfusion model to investigate the mechanisms of microglial activation following different degrees of global ischemia. Our results showed that the proliferation of microglia was gated by the degree of ischemia. Marked microglial de-ramification and proliferation were observed after 60 min of ischemia but not in transient ischemia (20 min). Immunohistology, qRT-PCR, and Western blotting analysis showed that microglial activation was accompanied with a reduction in Wnt/β-catenin signaling after cerebral ischemia. Downregulation of Wnt/β-catenin signaling using Wnt antagonist XAV939 during 20 min ischemia promoted microglial de-ramification and proliferation. In contrast, enhancing Wnt/β-catenin signaling using Wnt agonist LiCl during 60 min ischemia-reduced microglial de-ramification and proliferation. Importantly, we found that Wnt agonist inhibited inflammation in the ischemic brain and was conducive to animal behavioral recovery. Collectively, these data demonstrated that Wnt/β-catenin signaling played a key role in microglial activation following cerebral ischemia, and regulating microglial activation may be a potential therapeutic strategy for the treatment of ischemic stroke.

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Data Availability

The data supporting the conclusions of this article are available from the corresponding author upon reasonable request.

Abbreviations

CNS:

central nervous system

JAK:

Janus-activated kinase

STAT:

signal transducer and activator of transcription

IFN-γ:

interferon-γ

TLR:

toll-like receptors

CSF1R:

colony-stimulating factor 1 receptor

Lef1:

lymphoid enhancer-binding factor 1

Ctnnb1:

catenin beta 1

TCF7L2:

transcription factor 7-like 2

Fzd9:

frizzled 9

TCF1:

T cell factor 1

Arg1:

arginase-1

TGFβ:

transforming growth factor beta

IL-1β:

interleukin 1-beta

IL-4:

interleukin 4

IL-6:

interleukin 6

iNOS:

inducible nitric oxide synthase

BCAL:

bilateral common carotid artery ligation

BCCA:

bilateral common carotid arteries

CBF:

cerebral blood flow

LSI:

laser speckle contrast imaging

FBS:

fetal bovine serum

PBS:

phosphate-buffered saline

OGD/R:

oxygen-glucose deprivation and reoxygenation

DMSO:

dimethyl sulfoxide

PFA:

paraformaldehyde

BrdU:

bromodeoxyuridine

MCAO:

middle cerebral occlusion

RT-qPCR:

quantitative real-time polymerase chain reaction

GFP:

green fluorescent protein

ROI:

region of interest

PU.1:

Spi-1 proto-oncogene

Irf8:

interferon regulatory factor 8

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Acknowledgements

The authors thank Lei Wang, Liang Peng, and Li** Guan at the Core Facility of School of Life Sciences, Lanzhou University, for excellent technical assistance.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82271402), the Natural Science Foundation of Gansu Province (No. 22JR5RA437), and the Excellent Graduate Student “Innovation Star” Program of Education Department of Gansu Province (No. 2021CXZX-027).

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  1. Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, 730000, China

    Junru Liu, **nying Zhang, Yanyi Xu & Shengxiang Zhang

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JRL and SXZ designed the research plan; JRL, XYZ, and YYX performed the experiments; JRL, XYZ, and YYX analyzed the data; JRL and SXZ wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Shengxiang Zhang.

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Liu, J., Zhang, X., Xu, Y. et al. Regulation of Microglial Activation by Wnt/β-Catenin Signaling After Global Cerebral Ischemia in Mice. Mol Neurobiol 61, 308–325 (2024). https://doi.org/10.1007/s12035-023-03557-8

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