Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2018 Mar 19;9:523. doi: 10.3389/fimmu.2018.00523. eCollection 2018.
Astrocyte loss induced by neuromyelitis optica (NMO)-IgG and complement-dependent cytotoxicity (CDC) is the hallmark of NMO pathology. The survival of astrocytes is thought to reflect astrocyte exposure to environmental factors in the CNS and the response of astrocytes to these factors. However, still unclear are how astrocytes respond to NMO-IgG and CDC, and what CNS environmental factors may impact the survival of astrocytes. In a murine model of NMO induced by intracerebral injection of NMO-IgG and human complement, we found dramatic upregulation of IL-15 in astrocytes. To study the role of astrocytic IL-15 in NMO, we generated a transgenic mouse line with targeted expression of IL-15 in astrocytes (IL-15), in which the expression of IL-15 is controlled by a glial fibrillary acidic protein promoter. We showed that astrocyte-targeted expression of IL-15 attenuates astrocyte injury and the loss of aquaporin-4 in the brain. Reduced blood-brain barrier leakage and immune cell infiltration are also found in the lesion of IL-15 mice subjected to NMO induction. IL-15 astrocytes are less susceptible to NMO-IgG-mediated CDC than their wild-type counterparts. The enhanced resistance of IL-15 astrocytes to cytotoxicity and cell death involves NF-κB signaling pathway. Our findings suggest that IL-15 reduces astrocyte loss and NMO pathology.
视神经脊髓炎（NMO）-IgG 和补体依赖性细胞毒性（CDC）诱导的星形胶质细胞丢失是 NMO 病理学的标志。星形胶质细胞的存活被认为反映了星形胶质细胞在中枢神经系统中暴露于环境因素以及星形胶质细胞对这些因素的反应。然而，仍不清楚星形胶质细胞如何对 NMO-IgG 和 CDC 作出反应，以及中枢神经系统环境因素可能如何影响星形胶质细胞的存活。在 NMO-IgG 和人补体脑内注射诱导的 NMO 小鼠模型中，我们发现星形胶质细胞中 IL-15 的表达显著上调。为了研究星形胶质细胞 IL-15 在 NMO 中的作用，我们生成了一种靶向表达星形胶质细胞中 IL-15 的转基因小鼠系（IL-15），其中 IL-15 的表达受胶质纤维酸性蛋白启动子控制。我们发现，星形胶质细胞靶向表达 IL-15 可减轻脑内星形胶质细胞损伤和水通道蛋白-4 的丢失。在 NMO 诱导的 IL-15 小鼠病变中，还发现血脑屏障渗漏和免疫细胞浸润减少。与野生型相比，IL-15 星形胶质细胞对 NMO-IgG 介导的 CDC 的敏感性降低。IL-15 星形胶质细胞对细胞毒性和细胞死亡的增强抗性涉及 NF-κB 信号通路。我们的研究结果表明，IL-15 可减少星形胶质细胞丢失和 NMO 病理学。
