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效应的关键特征。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已经证明了在实验和临床中风后，急性期外周免疫的强烈过度激活和慢性期的低度慢性炎症状态。这些发现产生了急性卒中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，脑释放的alarmins -从坏死脑组织释放的促炎分子-是中风后引发这种多相外周免疫稳态失衡的关键介质。脑卒中患者的发病率和死亡率与免疫机制密切相关。该项目的总体目的是研究alarmins作为中风患者在中风后免疫级联反应的不同阶段观察到的多种关键合并症的上游介质的作用。因此，我们假设大脑释放的alarmins可能在介导以下过程中发挥关键作用：1）由于alarmins驱动的急性脑风暴，急性期的复杂行为变化-称为脑诱发的疾病行为。2)在亚急性期，由于适应性免疫细胞的半胱天冬酶1-依赖性热凋亡细胞死亡和中风后对细菌感染的易感性增加，免疫表型从免疫激活转变为抑制。3)由于alarmin介导的免疫稳态失衡和慢性炎症，中风后慢性阶段动脉粥样硬化的恶化。本项目的目的是研究alarmins在介导中风的这些关键合并症--疾病行为、免疫抑制和慢性血管炎症--在中风后的不同阶段中的潜在作用。我们将分析这些新疾病途径的潜在机制和潜在药物靶点。更好地理解卒中后alarmin驱动的免疫级联反应与潜在的临床应用具有直接的翻译相关性。研究的三种卒中合并症导致了很大比例的卒中后并发症和发病率，并且可能有一个共同的触发因素：卒中后促炎性警报素的释放。

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.