Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway

Abstract

Background

Cerebral infarction often results in post-stroke cognitive impairment, which impairs the quality of life and causes long-term disability. Astrocytes, the most abundant glial cells in the central nervous system, have a crucial role in cerebral ischemia and neuroinflammation. We explored the possible advantages of interleukin-6 (IL-6), a powerful pro-inflammatory cytokine produced by astrocytes, for post-stroke cognitive function.

Methods

Mendelian randomization was applied to analyze the GWAS database of stroke patients, obtaining a causal relationship between IL-6 and stroke. Further validation of this relationship and its mechanisms was conducted. Using a mouse model of cerebral infarction, we demonstrated a significant increase in IL-6 expression in astrocytes surrounding the ischemic lesion. This protective effect of Piezo1 knockout was attributed to the downregulation of matrix metalloproteinases and upregulation of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1).

Results

Two-step Mendelian randomization revealed that IL-6 exposure is a risk factor for stroke. Moreover, we conducted behavioral assessments and observed that Piezo1 knockout mice that received intranasal administration of astrocyte-derived IL-6 showed notable improvement in cognitive function compared to control mice. This enhancement was associated with reduced neuronal cell death and suppressed astrocyte activation, preserving ZO-1.

Conclusion

Our study shows that astrocyte-derived IL-6 causes cognitive decline after stroke by protecting the blood-brain barrier. This suggests that piezo1 knockout may reduce cognitive impairment after brain ischemia. Further research on the mechanisms and IL-6 delivery methods may lead to new therapies for post-stroke cognition.

Keywords:

• cerebral infarction
• neuroinflammation
• astrocytes
• blood-brain barrier
• tight junctions

Abbreviations

IL-6, interleukin-6; GPX4, glutathione peroxidase 4; ZO-1, zonula occludens-1; BBB, blood-brain barrier; GABA, glutamate and gamma-aminobutyric acid; SNPs, single nucleotide polymorphisms; IVs, instrumental variables; LD, linkage disequilibrium; SE, standard error;ANOVA, analysis of variance; TSMA, Two-Sample Mendelian Randomization Analysis.

Data Sharing Statement

Data can be provided if necessary. The data is available from the first authors (Lujia Tang and Di Xie).

Ethics Approval and Consent to Participate

This study was approved by the Animal Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, with an ethics number of 2021-028. The researchers stated they strictly comply with the national laws (the People’s Republic of China National Standard GB/T 35892-2018).

Consent to Publish

All authors agreed to publish.

Disclosure

The authors have declared that no competing interest exists.

Additional information

Funding

This work was Sponsored by Program of Shanghai Academic Leader, Grant Number 21XD1402200; the Shanghai Committee of Science and Technology, Grant No. 23YF1425200; and National Natural Science Foundation of China, Grant Number 82072207.