The role of the nuclear receptor NR4A1 in acute ischemic stroke: pathophysiology, therapeutic evaluation and human translation

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The treatment of ischemic stroke has significantly improved by using modern revascularization therapies. Nevertheless, the majority of patients is not suitable for these therapies or has an unfavorable outcome despite revascularization. However, the growing knowledge on the pathophysiology of ischemic injury paved the way for new therapeutic options. In particular, the local inflammatory response after cerebral ischemia was identified as promising therapeutic target, which can be, in contrast to classic neuroprotective strategies, effectively modulated beyond the acute phase of ischemia. In this context, nuclear receptors, which play an important role in regulating inflammation and their ligands are attractive candidates for therapeutic interventions.Our preliminary data show for the first time that the nuclear receptor NR4A1 is involved in the pathophysiology of acute stroke. After experimental stroke NR4A1-/- mice have larger infarcts and a worse neurological outcome and vice versa wildtype mice treated with the NR4A1 agonist Cytosporone B have better outcomes suggesting a strong protective mode action of NR4A1. We identified increased neutrophil infiltration into the ischemic brain in NR4A1-/- mice as well as an increased proliferation and cytokine production of T cells as potential underlying mechanisms. These findings are surprising as a major role of NR4A1-/- in neutrophil or T cell functions was not yet demonstrated. Whether NR4A1 is a modulator of neutrophil function in the first place or neutrophil recruitment to the brain is increased in a T cell dependent manner is yet unknown and will be investigated in the proposed project. The overarching aim of this proposal is to elucidate the role of NR4A1 in the pathophysiology of ischemic stroke and to evaluate its potential suitability for future therapeutic interventions. First, we will identify the cellular mediators (neutrophils or T cells) of NR4A1 mediated neuroprotection using bone marrow chimeric mice, adoptive cell transfer, and cell specific knockout mice. Next, aiming at determining the molecular mechanisms, comprehensive analyses of such identified NR4A1-/- cellular mediators will be performed including functional analyses and studies on cell metabolism. In addition, SPECT imaging will be used for a detailed characterization of brain neutrophil infiltration. In order to evaluate the therapeutic applicability, a treatment with the NR4A1 agonist Cytosporone B will be initiated at different time points after ischemia onset in mice. To bridge the gap between our experimental studies and human stroke we will perform comprehensive studies on NR4A1 expression in patient brain tissue and blood immune cells as well as evaluate the effect of Cytosporone B on blood immune cells of patients. In summary, the proposed project allows for the identification of novel functions of NR4A1 in general and in the context of cerebral ischemia and will determine its suitability as therapeutic target.