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

作　　者：Wei Zhang Yubao Lu Ruoqi Shen Yingjie Wu Chenrui Liu Xingxing Fang Liangming Zhang Bin Liu Limin Rong 

机构地区：[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

出　　处：《Neural Regeneration Research》2025年第10期2955-2968,共14页中国神经再生研究（英文版）

基　　金：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);the National Natural Science Foundation of China,Nos.81972111(to LZ),81772349(to BL).

摘　　要：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.

关 键 词：ceramide synthase 5 gasdermin D MICROGLIA NEUROINFLAMMATION NLRP3 nuclear factor kappa B Pla2g7 PYROPTOSIS sphingomyelin metabolism spinal cord injury 

分 类 号：R651.2[医药卫生—外科学]