Decoding IL-17A-mediated influences on stroke recovery

在中风中，高度保守的细胞因子IL-17 A是放大缺血组织中有害的缺血后炎症反应的关键。同时，IL-17 A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。虽然IL-17 A的免疫致病作用已清楚地显示在中风中，目前尚不清楚是否不同的CNS驻留细胞差异感测和反应IL-17 A，从而确定神经元再生。因此，该项目的总体目标是了解高度保守的细胞因子IL-17 A如何决定卒中结局。我们的目标是破译缺血性脑组织中IL-17 A的细胞来源，以及IL-17 A是否支配神经元和星形胶质细胞信号通路，从而改变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IL 17 A及其受体的细胞类型特异性缺失和细胞类型特异性转录组学结合联合收割机。最终，新组装的基因网络将在小鼠和人类神经元细胞培养物中进行验证和机制探索，这些细胞培养物受到谷氨酸和氧-葡萄糖剥夺的挑战。因此，我们期望鉴定出直接受IL-17 A调节或在感受到IL-17 A后间接受星形胶质细胞输出调节并决定斯托克结局的神经元内在基因。我们设想这些可能是改善中风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.