Brain-released alarmins as mediators of immunological comorbidities after stroke

外周免疫系统的改变是急性卒中后全身影响的一个关键特征。卒中后免疫调节的一个突出现象是卒中后亚急性期的免疫抑制综合征。然而，申请人和其他人最近的工作表明，实验性和临床卒中后急性期外周免疫功能强烈过度激活，慢性期处于低度慢性炎症状态。这些发现产生了对急性中风的多相系统免疫反应的新概念。我们在最近的一项原则验证研究中表明，脑内释放的致炎分子--从坏死的脑组织中释放的促炎分子--是中风后外周免疫平衡多相失衡的关键介质。免疫学机制在很大程度上导致了中风患者的发病率和死亡率。该项目的总体目标是研究在卒中后免疫级联反应的不同阶段，在卒中患者中观察到的多种危重合并症的上游调节因子的作用。因此，我们推测大脑释放的警报蛋白可能在以下调节中起到关键作用：1)由于警报蛋白驱动的急性细胞因子风暴，在急性期复杂的行为变化--称为细胞因子诱导的疾病行为。2)由于适应性免疫细胞依赖caspase-1的焦链细胞死亡，导致卒中后细菌感染易感性增加，亚急性期免疫表型由免疫激活向抑制转变。3)卒中后慢性期动脉粥样硬化的加重是由于警报蛋白的介导、免疫平衡失衡和慢性炎症。本项目的目的是调查在卒中后不同阶段的这些关键共病--中风后的疾病行为、免疫抑制和慢性血管炎症--中，警报在这些关键共病中的潜在作用。我们将分析这些新疾病途径的潜在机制和潜在的药物靶点。更好地了解卒中后警报蛋白驱动的免疫级联反应具有潜在的临床应用的直接翻译相关性。被调查的三种卒中合并症导致了卒中后并发症和发病率的很大比例，并且可能有一个共同的触发因素：卒中后促炎性警报的释放。

Alteration of the peripheral immune system is a key feature of systemic effects after acute stroke. One prominent phenomenon of post-stroke immunomodulation is an immunosuppressive syndrome in the subacute phase after stroke. However, recent works by the applicant and others have demonstrated a strong over-activation of peripheral immunity in the acute phase and a low-grade chronic inflammatory state in the chronic phase after experimental and clinical stroke. These findings have generated the novel concept of a multiphasic systemic immune reaction to acute stroke. We have shown in a recent proof-of-principle study that brain-released alarmins - pro-inflammatory molecules released from necrotic brain tissue - are key mediators initiating this multiphasic dysbalance of peripheral immune homeostasis after stroke. Immunological mechanisms contribute substantially to morbidity and mortality of stroke patients. The general aim of this project is to investigate the role of alarmins as an upstream mediator of multiple critical comorbidities observed in stroke patients at distinct phases within the immunological cascade after stroke. Therefore, we hypothesize that brain-released alarmins might play a crucial role in mediating: 1) the complex behavioral changes in the acute phase - known as cytokine-induced sickness-behavior - due to an alarmin-driven acute cytokine-storm. 2) the immunophenotypical switch from immune activation to suppression in the subacute phase due to caspase 1-dependent pyroptotic cell death of adaptive immune cells and cause of increased susceptibility to bacterial infections after stroke. 3) the exacerbation of atherosclerosis in the chronic stages after stroke due to alarmin-mediated, dysbalanced immune homeostasis and chronic inflammation. The purpose of this project is to investigate the potential role of alarmins in mediating these critical comorbidities of stroke - sickness behavior, immunosuppression and chronic vascular inflammation - in their distinct phases after stroke. We will analyze the underlying mechanisms and potential drug targets in these novel disease pathways. Better understanding of alarmin-driven immunological cascades after stroke are of direct translational relevance with potential clinical use. The three investigated stroke comorbidities contribute to a large proportion of post-stroke complications and morbidity and might have one common trigger: the release of pro-inflammatory alarmins after stroke.