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Circular RNA Hecw1 Regulates the Inflammatory Imbalance in Spinal Cord Injury via miR-3551-3p/LRRTM1 Axis

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Spinal cord injury (SCI) is a neurological disease having devastating effect and results in the development of systemic inflammation. However, the molecular mechanisms of SCI remain not entirely elucidated. This study was directed toward exploring the circ Hecw1 involved in the mechanism of lipopolysaccharide (LPS)-triggered inflammation damage in neuronal cells. The in vitro model of SCI based on PC12 cells were established with lipopolysaccharide. The cell proliferation was determined by the use of cell counting kit-8 (CCK8). The expressions of circHecw1, miR-3551-3p, and inflammatory factors were measured by quantitative real-time PCR and ELISA assay. Flow cytometry was used to assess apoptosis. Western blot analysis was performed for the purpose of determining LRRTM1 and NF-kB signaling. The expression of circ Hecw1, TNF-α, IL-6, and IL-1β in LPS-triggered PC12 cells and the expression of miR-3551-3p and IL-10 were significantly decreased. Knockdown of circHecw1 promoted proliferation and inhibited apoptosis and reduction in the inflammatory cytokine expression. Our study revealed that circHecw1 regulates SCI neuronal cell inflammation imbalance by regulating the miR-3551-3p/LRRTM1 signaling.

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  1. Kobayakawa, K., Ohkawa, Y., Yoshizaki, S., et al. (2019). Macrophage centripetal migration drives spontaneous healing process after spinal cord injury. Sci Adv., 5(5), eaav5086.

    Article  CAS  Google Scholar 

  2. Koda, M., Hanaoka, H., Fujii, Y., et al. (2021). Randomized trial of granulocyte colony-stimulating factor for spinal cord injury. Brain, 144(3), 789–799.

    Article  Google Scholar 

  3. Gao, C., Yin, F., Li, R., et al. (2021). MicroRNA-145-mediated KDM6A downregulation enhances neural repair after spinal cord injury via the NOTCH2/Abcb1a axis. Oxidative Medicine and Cellular Longevity, 2021, 2580619.

    Article  Google Scholar 

  4. Ruzicka, J., Romanyuk, N., Jirakova, K., et al. (2019). The effect of iPS-derived neural progenitors seeded on laminin-coated pHEMA-MOETACl hydrogel with dual porosity in a rat model of chronic spinal cord injury. Cell Transplantation, 28(4), 400–412.

    Article  Google Scholar 

  5. Cheng Z, Zhu W, Cao K, et al. (2016). Anti-inflammatory mechanism of neural stem cell transplantation in spinal cord injury. Int J Mol Sci. 17(9).

  6. Anjum A, Yazid MD, Fauzi Daud M, et al. (2020). Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 21(20).

  7. Lin, Z. H., Wang, S. Y., Chen, L. L., et al. (2017). Methylene blue mitigates acute neuroinflammation after spinal cord injury through inhibiting NLRP3 inflammasome activation in microglia. Frontiers in Cellular Neuroscience, 11, 391.

    Article  Google Scholar 

  8. Zhang, Y., Zhou, Y., Chen, S., et al. (2019). Macrophage migration inhibitory factor facilitates prostaglandin E(2) production of astrocytes to tune inflammatory milieu following spinal cord injury. Journal of Neuroinflammation, 16(1), 85.

    Article  Google Scholar 

  9. Chen, W. K., Feng, L. J., Liu, Q. D., et al. (2020). Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model. Journal of Neuroinflammation, 17(1), 202.

    Article  CAS  Google Scholar 

  10. Lee, J. S., Hsu, Y. H., Chiu, Y. S., Jou, I. M., & Chang, M. S. (2020). Anti-IL-20 antibody improved motor function and reduced glial scar formation after traumatic spinal cord injury in rats. Journal of Neuroinflammation, 17(1), 156.

    Article  CAS  Google Scholar 

  11. Li, Q., Li, B., Tao, B., et al. (2021). Identification of four genes and biological characteristics associated with acute spinal cord injury in rats integrated bioinformatics analysis. Ann Transl Med., 9(7), 570.

    Article  CAS  Google Scholar 

  12. Li, X., Kang, J., Lv, H., et al. (2021). CircPrkcsh, a circular RNA, contributes to the polarization of microglia towards the M1 phenotype induced by spinal cord injury and acts via the JNK/p38 MAPK pathway. The FASEB Journal, 35(12), e22014.

    Article  CAS  Google Scholar 

  13. Fu, X., Zeng, H., Zhao, J., et al. (2021). Inhibition of Dectin-1 ameliorates neuroinflammation by regulating microglia/macrophage phenotype after intracerebral hemorrhage in mice. Translational Stroke Research, 12(6), 1018–1034.

    Article  CAS  Google Scholar 

  14. Fei, M., Li, Z., Cao, Y., Jiang, C., Lin, H., & Chen, Z. (2021). MicroRNA-182 improves spinal cord injury in mice by modulating apoptosis and the inflammatory response via IKKβ/NF-κB. Laboratory Investigation, 101(9), 1238–1253.

    Article  CAS  Google Scholar 

  15. Liu, H., Zhang, J., Xu, X., et al. (2021). SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. Theranostics., 11(9), 4187–4206.

    Article  CAS  Google Scholar 

  16. Feng, D., Yu, J., Bao, L., Fan, D., & Zhang, B. (2021). Inhibiting RGS1 attenuates secondary inflammation response and tissue degradation via the TLR/TRIF/NF-κB pathway in macrophage post spinal cord injury. Neuroscience Letters, 768, 136374.

    Article  Google Scholar 

  17. Slack, F. J., & Chinnaiyan, A. M. (2019). The role of non-coding RNAs in oncology. Cell, 179(5), 1033–1055.

    Article  CAS  Google Scholar 

  18. Hombach, S., & Kretz, M. (2016). Non-coding RNAs: Classification, biology and functioning. Advances in Experimental Medicine and Biology, 937, 3–17.

    Article  CAS  Google Scholar 

  19. Zhang, S. B., Lin, S. Y., Liu, M., et al. (2019). CircAnks1a in the spinal cord regulates hypersensitivity in a rodent model of neuropathic pain. Nature Communications, 10(1), 4119.

    Article  Google Scholar 

  20. Zhou, J., Xiong, Q., Chen, H., Yang, C., & Fan, Y. (2017). Identification of the spinal expression profile of non-coding RNAs involved in neuropathic pain following spared nerve injury by sequence analysis. Frontiers in Molecular Neuroscience, 10, 91.

    Article  Google Scholar 

  21. Zhao, R. T., Zhou, J., Dong, X. L., et al. (2018). Circular ribonucleic acid expression alteration in exosomes from the brain extracellular space after traumatic brain injury in mice. Journal of Neurotrauma, 35(17), 2056–2066.

    Article  Google Scholar 

  22. Zhou, Z. B., Du, D., Chen, K. Z., Deng, L. F., Niu, Y. L., & Zhu, L. (2019). Differential expression profiles and functional predication of circular ribonucleic acid in traumatic spinal cord injury of rats. Journal of Neurotrauma, 36(15), 2287–2297.

    Article  Google Scholar 

  23. Pei, J. P., Fan, L. H., Nan, K., Li, J., Dang, X. Q., & Wang, K. Z. (2017). HSYA alleviates secondary neuronal death through attenuating oxidative stress, inflammatory response, and neural apoptosis in SD rat spinal cord compression injury. Journal of Neuroinflammation, 14(1), 97.

    Article  Google Scholar 

  24. Wu, W., Li, X., Yang, Z., et al. (2021). Specific microstructural changes of the cervical spinal cord in syringomyelia estimated by diffusion tensor imaging. Science and Reports, 11(1), 5111.

    Article  Google Scholar 

  25. Zhu, S., Chen, M., Chen, M., et al. (2020). Fibroblast growth factor 22 inhibits ER stress-induced apoptosis and improves recovery of spinal cord injury. Frontiers in Pharmacology, 11, 18.

    Article  CAS  Google Scholar 

  26. Zhu, S., Chen, M., Deng, L., et al. (2020). The repair and autophagy mechanisms of hypoxia-regulated bFGF-modified primary embryonic neural stem cells in spinal cord injury. Stem Cells Translational Medicine, 9(5), 603–619.

    Article  CAS  Google Scholar 

  27. Adhikary, S., Li, H., Heller, J., et al. (2011). Modulation of inflammatory responses by a cannabinoid-2-selective agonist after spinal cord injury. Journal of Neurotrauma, 28(12), 2417–2427.

    Article  Google Scholar 

  28. Orr, M. B., & Gensel, J. C. (2018). Spinal cord injury scarring and inflammation: Therapies targeting glial and inflammatory responses. Neurotherapeutics, 15(3), 541–553.

    Article  CAS  Google Scholar 

  29. Anwar, M. A., Al Shehabi, T. S., & Eid, A. H. (2016). Inflammogenesis of secondary spinal cord injury. Frontiers in Cellular Neuroscience, 10, 98.

    Article  Google Scholar 

  30. Pan, Z., Li, G. F., Sun, M. L., et al. (2019). MicroRNA-1224 splicing CircularRNA-Filip1l in an Ago2-dependent manner regulates chronic inflammatory pain via targeting Ubr5. Journal of Neuroscience, 39(11), 2125–2143.

    Article  CAS  Google Scholar 

  31. Peng, P., Zhang, B., Huang, J., et al. (2020). Identification of a circRNA-miRNA-mRNA network to explore the effects of circRNAs on pathogenesis and treatment of spinal cord injury. Life Sciences, 257, 118039.

    Article  CAS  Google Scholar 

  32. Wang, W., Su, Y., Tang, S., et al. (2019). Identification of noncoding RNA expression profiles and regulatory interaction networks following traumatic spinal cord injury by sequence analysis. Aging (Albany NY), 11(8), 2352–2368.

    Article  CAS  Google Scholar 

  33. Wu, R., Mao, S., Wang, Y., et al. (2019). Differential circular RNA expression profiles following spinal cord injury in rats: A temporal and experimental analysis. Frontiers in Neuroscience, 13, 1303.

    Article  Google Scholar 

  34. Liu, Y., Liu, J., & Liu, B. (2020). Identification of circular RNA expression profiles and their implication in spinal cord injury rats at the immediate phase. Journal of Molecular Neuroscience, 70(11), 1894–1905.

    Article  CAS  Google Scholar 

  35. Chen, J., Fu, B., Bao, J., Su, R., Zhao, H., & Liu, Z. (2021). Novel circular RNA 2960 contributes to secondary damage of spinal cord injury by sponging miRNA-124. The Journal of Comparative Neurology, 529(7), 1456–1464.

    Article  CAS  Google Scholar 

  36. Zhao, J., Qi, X., Bai, J., Gao, X., & Cheng, L. (2020). A circRNA derived from linear HIPK3 relieves the neuronal cell apoptosis in spinal cord injury via ceRNA pattern. Biochemical and Biophysical Research Communications, 528(2), 359–367.

    Article  CAS  Google Scholar 

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This work was sponsored by National Natural Science Foundation of China (81972061), National Natural Science Foundation of China (81871766), National Natural Science Foundation of China (81871776), and National Key Research and Development Project of Stem Cell and Transformation Research (2019YFA0112100).

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Correspondence to Yang Liu.

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Ban, D., Xiang, Z., Yu, P. et al. Circular RNA Hecw1 Regulates the Inflammatory Imbalance in Spinal Cord Injury via miR-3551-3p/LRRTM1 Axis. Appl Biochem Biotechnol 194, 5151–5166 (2022).

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