Wang Danjie, Zhang Tongtong, Shao Qi, Wu Xinyi, Zhao Xiaoqiang, Zhang Hongyu, Wang Yumeng, Sun Jingxian, Chang Xuechun, Zhu Keying, Wu Shuai, Cao Li, Chen Wankun, Wang Jun
Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, State Key Laboratory of Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education, NMU, Shanghai, China.
Cell Death Differ. 2025 Jun 25. doi: 10.1038/s41418-025-01537-0.
Demyelination, a hallmark of multiple sclerosis (MS), disrupts neural conduction due to myelin sheath degradation. Microglia-mediated inflammation plays a pivotal role in this process, with emerging evidence implicating gasdermin E (GSDME) in neuroinflammation and neurodegeneration. However, the specific role of GSDME in MS remains unclear. Here, we investigated the involvement of GSDME in MS using brain tissues from MS patients and cuprizone (CPZ)-induced demyelination model mice. We observed elevated GSDME expression in the central nervous system (CNS) lesions of MS patients, with pronounced GSDME cleavage in microglia at injury sites. Genetic knockout of Gsdme alleviated CPZ-induced motor deficits, demyelination, and neuroinflammation. Furthermore, caspase-3 inhibition significantly suppressed GSDME activation, resulting in reduced demyelination, motor coordination impairment, and neuroinflammation. In an experimental autoimmune encephalomyelitis (EAE) model, caspase-3/GSDME-mediated microglial pyroptosis critically mediated the progression of neuroinflammation and white matter demyelination. Transcriptome sequencing revealed that GSDME regulated the expression of genes related to disease-associated microglia (DAMs) and impaired microglial autophagy, a process critical for myelin debris clearance. Gsdme knockout downregulated the expression of genes associated with DAMs and CPZ-induced microglia-driven demyelination while increasing the expression of remyelination-related genes (Cybb and Cd74). In vitro, GSDME suppression promoted microglial autophagy and myelin debris clearance. Collectively, our findings highlight GSDME-mediated pyroptosis as a key driver of demyelination and neuroinflammation in MS, suggesting novel therapeutic targets for neuroinflammatory disorders.
脱髓鞘是多发性硬化症（MS）的一个标志，由于髓鞘降解而破坏神经传导。小胶质细胞介导的炎症在这一过程中起关键作用，越来越多的证据表明gasdermin E（GSDME）参与神经炎症和神经退行性变。然而，GSDME在MS中的具体作用仍不清楚。在这里，我们使用MS患者的脑组织和 cuprizone（CPZ）诱导的脱髓鞘模型小鼠来研究GSDME在MS中的作用。我们观察到MS患者中枢神经系统（CNS）病变中GSDME表达升高，损伤部位的小胶质细胞中GSDME明显裂解。Gsdme基因敲除减轻了CPZ诱导的运动缺陷、脱髓鞘和神经炎症。此外，caspase-3抑制显著抑制GSDME激活，导致脱髓鞘减少、运动协调障碍和神经炎症减轻。在实验性自身免疫性脑脊髓炎（EAE）模型中，caspase-3/GSDME介导的小胶质细胞焦亡在神经炎症和白质脱髓鞘的进展中起关键作用。转录组测序显示，GSDME调节与疾病相关小胶质细胞（DAMs）相关的基因表达，并损害小胶质细胞自噬，这是清除髓鞘碎片的关键过程。Gsdme基因敲除下调了与DAMs相关的基因表达以及CPZ诱导的小胶质细胞驱动的脱髓鞘，同时增加了与再髓鞘化相关的基因（Cybb和Cd74）的表达。在体外，抑制GSDME促进小胶质细胞自噬和髓鞘碎片清除。总的来说，我们的研究结果突出了GSDME介导的焦亡是MS中脱髓鞘和神经炎症的关键驱动因素，为神经炎症性疾病提供了新的治疗靶点。
