Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (10): 2955-2968.doi: 10.4103/NRR.NRR-D-23-01933

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Inhibiting ceramide synthase 5 expression in microglia decreases neuroinflammation after spinal cord injury

Wei Zhang1, 2, 3, 4, #, Yubao Lu1, 2, 3, 4, #, Ruoqi Shen1, #, Yingjie Wu1 , Chenrui Liu1 , Xingxing Fang1 , Liangming Zhang1, 2, 3, 4, *, Bin Liu1, 2, 3, 4, *, Limin Rong1, 2, 3, 4, *   

  1. 1 Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China;  2 National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China;  3 Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China;  4 Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
  • Online:2025-10-15 Published:2025-02-09
  • Contact: Liangming Zhang, MD, PhD, zhanglm36@mail.sysu.edu.cn; Bin Liu, MD, PhD, liubin6@mail.sysu.edu.cn; Limin Rong, MD, PhD, ronglm@mail.sysu.edu.cn.
  • Supported by:
    This work was supported by grants from the National Key Research and Development Program of China, No. 2017YFA0105400 (to LR); the Key Research and Development Program of Guangdong Province, No. 2019B020236002 (to LR); and the National Natural Science Foundation of China, Nos. 81972111 (to LZ), 81772349 (to BL).

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Abstract: Microglia, the resident monocyte of the central nervous system, play a crucial role in the response to spinal cord injury. However, the precise mechanism remains unclear. To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury, we performed single-cell RNA sequencing dataset analysis, focusing on changes in microglial subpopulations. We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis, sphingomyelin metabolism, and neuroinflammation at high levels. Subsequently, we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury. Finally, we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells. Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis. Furthermore, ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway. Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function. Pla2g7 formed a “bridge” between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway. Collectively, these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3, thereby exerting neuroprotective effects.

Key words: ceramide synthase 5,  gasdermin D,  microglia,  neuroinflammation,  NLRP3,  nuclear factor kappa B,  Pla2g7,  pyroptosis,  sphingomyelin metabolism,  spinal cord injury