Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis
Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis
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DOI：
10.1073/pnas.1722041115
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发表时间：
2018-06-26
影响因子：
11.1
通讯作者：
Power, Christopher
中科院分区：
文献类型：
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作者：
McKenzie, Brienne A.;Mamik, Manmeet K.;Power, Christopher
多发性硬化症(MS)是一种原因不明的中枢神经系统进行性炎性脱髓鞘疾病，至今仍无法治愈。炎症体相关的半胱氨酸天冬氨酸氨基转移酶介导促炎症细胞因子IL-10和IL-18的成熟和释放，并激活成孔蛋白Gasdermin D(GSDMD)。炎症性程序性细胞死亡，即下垂，最近被证明是由GSDMD介导的。在这里，我们报道了GSDMD介导的炎性小体激活和下垂的分子证据，在MS患者和MS动物模型中，髓系细胞(巨噬细胞/小胶质细胞)和髓鞘形成少突胶质细胞(ODC5)意外地出现了实验性自身免疫性脑脊髓炎(EAE)。我们在体外观察了炎性刺激后人小胶质细胞和ODC5细胞中炎性小体的激活和下垂，并证明了小分子抑制剂VX-765对这两种细胞中caspase-1的抑制作用。通过siRNA转导抑制GSDMD抑制人小胶质细胞的上睑下垂。VX-765治疗EAE动物减少了中枢神经系统炎症小体和下垂相关蛋白的表达，防止了轴突损伤，并改善了神经行为表现。因此，GSDMD介导的选择性神经胶质细胞上睑下垂是一种先前未知的炎性脱髓鞘机制，为缓解MS和其他中枢神经系统炎症性疾病的疾病过程提供了独特的治疗机会。
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-10 and IL-18 and activate the pore-forming protein gasdermin D (GSDMD). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODC5) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODC5 in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.