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Brain-released alarmins as mediators of immunological comorbidities after stroke

脑释放的警报素作为中风后免疫合并症的介质

基本信息

批准号：
289539980
负责人：
Professor Dr. Arthur Liesz
金额：
--
依托单位：
Institut für Schlaganfall- und Demenzforschung (ISD)
依托单位国家：
德国
项目类别：
Independent Junior Research Groups
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/289539980?language=en
关键词：
Brain released alarmins mediators immunological

项目摘要

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.

外周免疫系统的改变是急性中风后全身效应的一个关键特征。中风后免疫调节的一个突出现象是中风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，在实验和临床中风后，急性期外周免疫强烈过度激活，慢性期出现低度慢性炎症状态。这些发现产生了针对急性中风的多相全身免疫反应的新概念。我们在最近的一项原理验证研究中表明，大脑释放的警报素（坏死脑组织释放的促炎分子）是中风后引发外周免疫稳态多相失衡的关键介质。免疫学机制对中风患者的发病率和死亡率有很大影响。该项目的总体目标是研究警报素作为中风后免疫级联不同阶段的中风患者中观察到的多种严重合并症的上游介质的作用。因此，我们假设大脑释放的警报素可能在介导以下方面发挥关键作用：1）急性期复杂的行为变化 - 称为细胞因子诱导的疾病行为 - 由于警报素驱动的急性细胞因子风暴。 2) 由于适应性免疫细胞的 caspase 1 依赖性焦亡细胞死亡，导致亚急性期免疫表型从免疫激活转变为抑制，并导致中风后对细菌感染的易感性增加。 3）由于警报素介导的免疫稳态失衡和慢性炎症，导致中风后慢性阶段动脉粥样硬化恶化。该项目的目的是研究警报素在调节中风后不同阶段的这些关键合并症（疾病行为、免疫抑制和慢性血管炎症）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药物靶点。更好地了解中风后警报素驱动的免疫级联反应与潜在的临床应用具有直接的转化相关性。所研究的三种中风合并症导致了中风后并发症和发病率的很大一部分，并且可能有一个共同的触发因素：中风后促炎警报素的释放。