Decoding IL-17A-mediated influences on stroke recovery

在卒中中，高度保守的细胞因子IL-17A对于扩大缺血组织中有害的缺血后炎症反应至关重要。同时，IL-17A具有重要的非免疫特性，对神经元和神经胶质细胞具有营养和稳态作用。尽管IL-17A在卒中中的免疫致病作用已被明确显示，但目前尚不清楚不同的中枢神经系统驻留细胞是否对IL-17A有不同的感知和反应，从而决定神经元的再生。因此，该项目的总体目标是了解高度保守的细胞因子IL-17A是如何决定中风结果的。我们的目标是破译缺血脑组织中IL-17A的细胞来源，以及IL-17A是否决定了神经元和星形胶质细胞的信号通路，从而改变了影响神经元功能的细胞基因网络。为此，我们将跟踪实验性中风后的长期表型结果，并将其与特定细胞类型的IL17A及其受体的缺失和特定细胞类型的转录片段相结合。最终，新组装的基因网络将在挑战谷氨酸和缺氧-葡萄糖剥夺的小鼠和人类神经细胞培养中得到验证和机械探索。因此，我们希望在检测到IL-17A之后，确定由IL-17A直接调节或由星形细胞输出间接调节的神经元内源性基因，并决定卒中结果。我们设想这些药物可能成为促进卒中后再生的潜在药物靶点。

In stroke, the highly conserved cytokine IL-17A is pivotal for the amplification of the detrimental postischemic inflammatory response in the ischemic tissue. At the same time, IL-17A holds important non-immune properties with trophic and homeostatic effects on neurons and glial cells. Although the immune-pathogenic role of IL-17A has clearly been shown in stroke, it is currently unknown whether different CNS-resident cells differentially sense and react to IL-17A and thereby determine neuronal regeneration. Therefore, the overall objective of the project is to understand how the highly conserved cytokine IL-17A dictates stroke outcome. We aim to decipher the cellular source of IL-17A in the ischemic brain tissue and whether IL-17A dictates neuronal and astrocytic signaling pathways, which alter cellular gene networks that influence neuronal functions. To do so, we will follow the long-term phenotypic outcome after experimental stroke and combine that with cell-type-specific deletions of IL17A and its receptor and cell-type-specific transcriptomics. Eventually, newly assembled gene networks will be validated and mechanistically explored in mouse and human neuronal cell cultures challenged with glutamate and oxygen-glucose deprivation. Thus, we expect to identify neuron-intrinsic genes that are directly regulated by IL-17A or indirectly by astrocytic output after sensing IL-17A and that determine stoke outcome. We envision that these could be potential drug targets to improve post-stroke regeneration.