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Inhibition of TLR4/NF-κB pathway and endoplasmic reticulum stress by overexpressed S100A4 ameliorates retinal ischemia-reperfusion injury of mice

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Abstract

Retinal ischemia exists in various ischemic retinopathies including glaucoma, contributing to the death of retinal neurons. Calcium binding protein S100A4 is important in tumors, and our previous study found that S100A4 protects retinal ganglion cells (RGCs) against retinal ischemia-reperfusion (I/R) injury. This study was aimed to further discuss the neuroprotection and mechanisms of S100A4 in retinal I/R of mice. The rAAV-EF1α-s100a4-EGFP-WPRE or rAAV-EF1α-EGFP-WPRE-Pa was injected intravitreally 4 weeks before I/R. S100A4, molecules in TLR4 signaling pathway and endoplasmic reticulum (ER) stress branches, inflammatory molecules, and surviving RGCs and cholinergic amacrine (ChAT) cells were determined by quantitative PCR, western blot, or immunofluorescent staining. The apoptosis and necrosis of retinal neurons induced by I/R were inhibited by overexpressed S100A4. RGCs, ChAT cells, and the retinal function were preserved by S100A4 overexpressing 7 days after I/R. Mechanistically, the beneficial effects of S100A4 may be mediated by inhibiting the activation of TLR4 signaling pathway and alleviating ER stress, leading to the attenuation of inflammatory response of the retina after I/R. Our findings indicated that S100A4 has neuroprotective effect against retinal I/R injury, and promoting S100A4 expression may be an effective strategy to inhibit retinal neurons from degeneration in ischemic retinopathy.

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Acknowledgements

The authors want to thank Dr. Xinlan Lei, Dr. Qinqin Deng, and Dr. Chen Zhao for their expert and constructive suggestions.

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  1. Jiayi Yang and Xiao Zhang contributed equally to this work.

Authors and Affiliations

  1. Ophthalmic Center, Renmin Hospital of Wuhan University, Wuhan, China

    Jiayi Yang, Xiao Zhang, Ying Li, Ning Yang, Jinyuan Luo, Tao He & Yiqiao Xing

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  1. Jiayi Yang
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  2. Xiao Zhang
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Contributions

Jiayi Yang and Xiao Zhang: Study design, data collection and analysis, figures and original draft writing. Ying Li: Data collection and figures. Jiayi Yang and Xiao Zhang: Data interpretation. Ning Yang and Jinyuan Luo: Editing the manuscript. Tao He and Yiqiao Xing: Supervision, Study design, and reviewing and editing the manuscript.

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Correspondence to Tao He or Yiqiao Xing.

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Yang, J., Zhang, X., Li, Y. et al. Inhibition of TLR4/NF-κB pathway and endoplasmic reticulum stress by overexpressed S100A4 ameliorates retinal ischemia-reperfusion injury of mice. Mol Neurobiol 61, 2228–2240 (2024). https://doi.org/10.1007/s12035-023-03709-w

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