Пиропотоз в микроглии, полученный при помощи ПБДМВ, усугубляет демиелинацию и нейрофламмацию в множестве склерозов: озарения людей и мышей модели обезвоживания, вызванной кубизоной.
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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
Аннотация
Оригинал публикации
GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice.
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.