巨噬细胞活化依赖TRPV1通道介导FSE引起的颞叶癫痫机制研究

Febrile seizures especially serious persistent seizures（such as febrile status epilepticus,FSE）can lead to cerebral ischemic anoxia and brian injury. Children who suffer febrile seizures continuous more than 30min will have neuronal ischemic damage, and have a high risk to temporal lobe epilepsy（TLE）. However, the intrinsic mechanism is still unknown. Inflammation mediation by immune cells is one of the important factors involved in nervous system diseases. lymphocyte, monocyte, macrophages, etc. induce febrile seizures through the secretion of variety of inflammatory cytokines such as IL - 1β, IL- 6 and TNF-α. Whether the peripheral immune cells directly involved in seizures via infiltrate into the central nervous system, is still controversial. Our previous results showed that TRPV1 channels can improve the secretion levels of IL - 1β, IL- 6 and TNF-α in febrile seizures mice brain,and the susceptibility of TRPV1 gene deficient mice reduced to PTZ after adults although they were suffered from repetitively febrile seizures in childhood. Therefore,whether TRPV1 regulate the macrophages infiltration to CNS inducing febrile status epilepticus, and lead to adulthood temporal lobe epilepsy caused by the detention of macrophages in CNS after FSE? In the present proposal,we will investigate the mechanisms of TRPV1 regulation of macrophages activation and migration into the brain during the period of febrile status epilepticus to adulthood temporal lobe epilepsy in mice. Elucidating the mechanism of febrile status epileptic susceptibility to temporal lobe epilepsy, which may lead to the identification of novel pharmacological targets for clinical prevention and therapeutic of febrile seiures and epilepsy.

热性惊厥特别是严重持续惊厥（如高热惊厥癫痫持续状态，FSE）可致脑缺氧、脑损伤，小儿惊厥持续30分钟以上可产生神经元缺血性改变，易发展为内侧颞叶癫痫（MTLE），但发病原因复杂，机制不明。免疫细胞介导的炎症是神经系统疾病的重要因素，它们通过分泌IL-1β、IL-6和TNF-α等炎性因子参与热性惊厥。外周免疫细胞是否浸润中枢参与惊厥发生，至今仍存在争议。我们前期工作发现，TRPV1通道提高脑内IL-1β、IL-6和TNF-α的分泌水平导致小鼠热性惊厥发作；缺失TRPV1基因的小鼠幼年患反复热性惊厥，成年后对PTZ诱导的癫痫敏感性下降。TRPV1是否通过调节巨噬细胞参与FSE，诱导其滞留中枢引起成年期MTLE的易感？本项目将从小鼠FSE到成年期MTLE发病期间，研究TRPV1如何调控巨噬细胞活化、迁移入脑，深入探讨FSE易感MTLE的机制，为认识和完善热性惊厥导致癫痫的病理生理机制提供依据。

热性惊厥特别是严重持续惊厥（如高热惊厥癫痫持续状态，FSE）可致脑缺氧、脑损伤，小儿惊厥持续30分钟以上可产生神经元缺血性改变，是引起新生儿缺血缺氧性脑病（Hypoxic ischemic encephalopathy, HIE）一个不可忽视的病因，这种持续性的缺血缺氧状态，将导致后期的严重后遗症---- 癫痫，特别是发展为内侧颞叶癫痫（MTLE）时，对患儿的预后及生活质量都有严重影响。新生儿脑供氧不足是引起缺血缺氧脑病的主要诱因并使其具有高发病率和高死亡率。免疫细胞介导的炎症是神经系统疾病的重要因素，参与中枢神经系统免疫的细胞主要是胶质细胞，除此之外，还有外周的免疫细胞也可通过破坏的血脑屏障进入中枢，与胶质细胞共同调控中枢炎症反应。.临床数据表明，在HIE患儿的血液中可以观察到IL-1β的明显上升。IL-1β参与加重了中枢炎症导致神经元的异常放电。而之前研究发现星型胶质细胞激活后可以分泌IL-1β，并且在一些疾病中其是IL-1β的主要来源。TRPV1是一类非选择性的阳离子通道，也是中枢神经炎症中一个重要的生物指标。本课题发现TRP家族的一个离子通道（TRPV1）在局部缺血缺氧脑组织中调控星型胶质细胞的激活以及IL-1β的分泌：即TRPV1促进缺血缺氧后星型胶质细胞的激活；TRPV1通过JAK2-STAT3这个通路调控IL-1β的转录；TRPV1通过促进NLRP3炎症小体的形成调控IL-1β的剪切与成熟。因此，调控TRPV1通道对调控中枢神经系统免疫稳态作用不可忽视，通过调控中枢免疫进而调控疾病的发生发展，减少或降低疾病及并发症的发生率。