缺血性脑卒中诱发的NK细胞介导的免疫功能变化及其机制

Ischemic stroke is one of the leading causes of disability and mortality in China. One of such reasons is that stroke induce immune deficiency which contributed to infection in patients. This great prevalence of infections in stroke patients begs greater understanding of how stroke influences lymphocyte-mediated immunity systemically and within the central nervous system. However, how stroke impact individual immune cells and underlying mechanisms are not clear. Natural killer (NK) cells of the innate immune systems provide the first line of defense against many pathogens, but the contribution of NK cells in post-stroke induced immune inhibition and the immune strategies in combating infection are not fully understood. Our preliminary data helps understand the features of NK cells in stroke. We have demonstrated that NK cells infiltrated in human and mouse brain, which subsequently influence the size of infarction in MCAO mouse model. So we hypothesis that stroke induce phenotypic and functional alteration of NK cells. So with our well-established tools to study NK cells, we will investigate the cellular immunity mediated by NK cells in Peripheral and central nervous system in ischemic stroke patients and MCAO mice. The outcome of this project will establish foundation of NK cell based therapies to combat stroke associated infections.

缺血性脑卒中是世界范围内主要致残和致死原因。卒中后免疫抑制导致易合并感染是患者致残和死亡的首要原因之一，然而卒中如何影响特定的免疫细胞亚群以及潜在机制尚未阐明。自然杀伤细胞（NK cell）是天然免疫及抗感染的第一道防线。申请者已发表的研究表明，缺血性脑卒中患者和动物模型脑内有NK细胞浸润，且与梗死体积相关。推测缺血性脑卒中能够通过改变NK细胞表型和功能，而影响脑梗死体积及患者预后。因此本课题应用课题组已确立的NK细胞研究策略，明确：1）缺血性脑卒中患者外周血NK细胞数量及生物学特征的变化；2）缺血性脑卒中小鼠模型外周及中枢神经系统NK细胞表型及功能改变；3）卒中引起NK细胞表型及功能改变的细胞以及分子机制。本研究旨在以NK细胞为例，更深入理解脑卒中所诱发的免疫缺陷机制，以减少卒中所引起的感染并发征，研究结果有望为应用 NK 细胞控制脑卒中后炎症及感染策略的研究奠定基础。

通过考察缺血性脑卒中患者外周血NK细胞表型及生物学特性变化，比较不同梗死体积及梗死时间与NK细胞表型和功能变化的关系。继而应用C57BL/6 (B6)小鼠大脑中动脉梗塞模型，研究了缺血性脑卒中引起NK细胞表型及功能变化的细胞以及分子机制。该研究揭示了控制这些不同器官免疫功能变化的神经通路和分子机制，进一步发现通过调控神经支配通路可减轻卒中患者感染的发生。该成果有助于更深入理解缺血性脑卒中所诱发的免疫缺陷机制，以减少卒中所引起的感染并发征；有望为应用 NK 细胞控制缺血性脑卒中后炎症及感染治疗策略的研究奠定基础.