Decoding IL-17A-mediated influences on stroke recovery

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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.