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<p>Pathological changes following spinal cord injury (SCI) are characterized by a gradual enlargement of the lesion area, often leading to cavity formation, accompanied by reactive astrocytic hyperplasia and chronic inflammation. Chronic inflammation tends to stimulate astrocyte activation and spinal cavity cavitation. Post-SCI inflammation primarily results from the activation of M1/M2 microglia, with M1 microglia inducing the death of reactive astrocytes in rats, thereby promoting inflammation. Additionally, the NLRP3 inflammasome is critically involved in the post-SCI inflammatory response, as its activation leads to the release of pro-inflammatory cytokines, further contributing to secondary injury and functional impairment. This study aimed to investigate the molecular mechanisms through which circular RNAs (circRNAs), influence the inflammatory response following spinal cord injury, particularly focusing on its role in modulating NLRP3 activation. Animal and cell models were established, and the success of the models and the secretion of factors were evaluated using the BBB locomotor rating scale, RT-qPCR, and WB. The circular structure of circGTF2H2C was verified through AGE, RNase R treatment, and actinomycin D treatment. Additionally, we investigated the interactions between circGTF2H2C and PTPN11, including the analysis of NLRP3 phosphorylation status through WB and Co-IP. Lastly, potential miRNA interactions with circGTF2H2C and PTPN11 were explored through RNA pull-down assays and luciferase reporter assays to confirm binding relationships. This study confirmed that circGTF2H2C was up-regulated in SCI tissues. Experimental results demonstrated that circGTF2H2C regulated the expression of pro-inflammatory factors IL-1β and IL-18. Further investigation revealed that circGTF2H2C played a pro-inflammatory role by regulating the phosphorylation level of NLRP3, while PTPN11 was also found to contribute to SCI induction. In addition, circGTF2H2C also affected SCI by competitively binding miR-1323 to up-regulate PTPN11. In summary, circGTF2H2C regulates NLRP3 dephosphorylation via PTPN11 in spinal cord injury, highlighting its potential as a target for therapeutic intervention.</p> Graphical Abstract <p></p>

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CircGTF2H2C Regulates NLRP3 Dephosphorylation via Modulating PTPN11 Expression in Spinal Cord Injury

  • 期刊论文

  • 发表日期：

    2025年4月16日

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  • Yong Wang,
  • Danyang Cai,
  • Jinsong Kong,
  • Ning Zhu,
  • Junhui Guan,
  • Zeyu Yang,
  • Shunjie Jia,
  • Jiehe Huang,
  • Wenbiao Zheng,
  • Xin Zheng

摘要

Pathological changes following spinal cord injury (SCI) are characterized by a gradual enlargement of the lesion area, often leading to cavity formation, accompanied by reactive astrocytic hyperplasia and chronic inflammation. Chronic inflammation tends to stimulate astrocyte activation and spinal cavity cavitation. Post-SCI inflammation primarily results from the activation of M1/M2 microglia, with M1 microglia inducing the death of reactive astrocytes in rats, thereby promoting inflammation. Additionally, the NLRP3 inflammasome is critically involved in the post-SCI inflammatory response, as its activation leads to the release of pro-inflammatory cytokines, further contributing to secondary injury and functional impairment. This study aimed to investigate the molecular mechanisms through which circular RNAs (circRNAs), influence the inflammatory response following spinal cord injury, particularly focusing on its role in modulating NLRP3 activation. Animal and cell models were established, and the success of the models and the secretion of factors were evaluated using the BBB locomotor rating scale, RT-qPCR, and WB. The circular structure of circGTF2H2C was verified through AGE, RNase R treatment, and actinomycin D treatment. Additionally, we investigated the interactions between circGTF2H2C and PTPN11, including the analysis of NLRP3 phosphorylation status through WB and Co-IP. Lastly, potential miRNA interactions with circGTF2H2C and PTPN11 were explored through RNA pull-down assays and luciferase reporter assays to confirm binding relationships. This study confirmed that circGTF2H2C was up-regulated in SCI tissues. Experimental results demonstrated that circGTF2H2C regulated the expression of pro-inflammatory factors IL-1β and IL-18. Further investigation revealed that circGTF2H2C played a pro-inflammatory role by regulating the phosphorylation level of NLRP3, while PTPN11 was also found to contribute to SCI induction. In addition, circGTF2H2C also affected SCI by competitively binding miR-1323 to up-regulate PTPN11. In summary, circGTF2H2C regulates NLRP3 dephosphorylation via PTPN11 in spinal cord injury, highlighting its potential as a target for therapeutic intervention.

Graphical Abstract