中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (on line): 1-16.

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SHP2 mediates glycolysis to regulate the phenotype of microglia and promote secondary inflammation of the spinal cord injury

  

  • 出版日期:2024-01-01 发布日期:2024-04-02

Xintian Ding1, 2, #, Chun Chen1, #, Heng Zhao1, #, Bin Dai1 , Lei Ye1, 2, Tao Song1 , Shuai Huang1 , Jia Wang1 , Tao You1, *   

  1. 1 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China; 2 Department of Orthopedics, Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui Province, China
  • Online:2024-01-01 Published:2024-04-02
  • Contact: Tao You, MD, PhD, youtao@ustc.edu.cn.
  • Supported by:
    This study was supported by the Anhui Province University Natural Science Research Project, No. 2023AH040394 (to TY); Hefei Comprehensive National Science Center Leading Medicine and Frontier Technology Research Institute Project, No. 2023IHM01073 (to TY); The Natural Science Foundation of Anhui Province, No. 2308085QH258 (to JW), and The Natural Science Foundation of Anhui Province, No. 2008085MH246 (to TY).

摘要: https://orcid.org/0000-0003-1774-3014 (Tao You)

Abstract: Spinal cord injury (SCI) encompasses both primary and secondary injuries, with mitigating secondary inflammation as a key therapeutic strategy. Microglia is integral to secondary inflammation. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is widely expressed in the human body and is involved in inflammation through various mechanisms. SHP2 is considered a potential target for the treatment of inflammation-related diseases, but its role in secondary inflammation caused by SCI has not been reported. In this study, SHP2 was found to be abundantly expressed in the microglia of SCI. Down-regulation of SHP2 in a lipopolysaccharide (LPS)-induced microglial inflammation model significantly attenuated the microglial inflammatory response. Notably, SCI mice treated with SHP2 inhibitors exhibited substantial improvements in Basso-Beattie-Bresnahan scoring for hindlimb function, along with reduced bladder residual urine volume. Furthermore, it was established that glycolysis predominantly fueled microglial inflammatory responses. SHP2 emerged as a crucial facilitator of microglial glycolysis, thereby regulating the microglial inflammatory phenotype. Co-culture model demonstrated that inflammatory factors produced by microglia led to neuronal apoptosis, while the inhibition of SHP2 expression could mitigate this effect. In conclusion, the present study demonstrates that SHP2 regulates glycolysis in microglia following SCI to mediate the phenotype of microglia, consequently impacting neuronal apoptosis. Therefore, the targeted inhibition of SHP2 emerges as a promising therapeutic avenue for attenuating secondary inflammation in microglia, presenting a potential target for SCI treatment.

Key words: spinal cord injury, glycolysis, SHP2, inflammation, microglia, inflammatory polarization, inflammatory response, neurons, apoptosis