Stroke induced-NK cell deficiency: mechanisms and clinical implications

中风诱导的 NK 细胞缺陷：机制和临床意义

基本信息

批准号：
9249129
负责人：
FU-DONG SHI
金额：
$ 40.6万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-06-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249129
关键词：
Acetylcholine Acute Adaptive Immune System Adoptive Transfer Adrenergic Agents Adrenergic Antagonists Alpha Cell Area Autopsy Bacterial Infections Brain Brain Infarction Brain Injuries Brain Ischemia Cause of Death Cells Cerebral Infarction Cerebral Ischemia Characteristics Clinical Competence Cytometry Cytotoxic T-Lymphocytes Development Event Exhibits Exposure to Fractalkine Frequencies Genetic High Prevalence Immune Immune response Immune system Immunity Immunocompetent Immunologic Deficiency Syndromes Immunosuppression Impairment Individual Infection Infiltration Inflammation Inflammatory Response Innate Immune System Interferons Intervention Ischemic Brain Injury Ischemic Stroke Lead Lesion Listeria monocytogenes Lymphocyte Lymphocyte Subset Lymphoid Magnetic Resonance Imaging Mediating Middle Cerebral Artery Occlusion Modeling Molecular Profiling Mus Myocardial Ischemia Natural Killer Cells Nervous system structure Neuraxis Neuroimmune Neurons Neurotransmitter Receptor Nicotinic Receptors Organ Outcome Pathway interactions Patients Pattern Peripheral Pharmacology Phenotype Process Recruitment Activity Risk Role Signal Transduction Spleen Stroke System T-Lymphocyte Subsets Testing Time Tomatoes Vascular blood supply base cholinergic clinically relevant combat cytokine cytotoxic design disability fighting genetic approach immune function immunological intervention improved interest liver function mortality mouse model neuroregulation neurotransmission novel strategies pathogen post stroke public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): Central nervous system (CNS)-infiltrating lymphocytes contribute to the progression of cerebral infarction in ischemic stroke. The damaged brain, in turn, exerts suppressive effects on the immune system. The temporal relationship of this reciprocal interaction between immune system and ischemic brain has not been defined, making immune intervention to limit brain damage exceedingly difficult. Moreover, the high prevalence of infection in stroke patients requires a better understanding of how stroke influences immune responses systemically and within the brain, to combat immune-related post-stroke complications. We recently showed that natural killer (NK) cells - a critical component of the innate immune system - are abundantly represented in peri-infarcted area of brain sections from autopsies of stroke patients. In a mouse model of cerebral ischemia, we showed that ischemic neuron-derived fractalkine recruited NK cells, which could accelerate brain infarction in the acute stage of ischemic stroke. Subsequently, NK cells exhibited decreased frequency and compromised function. Those NK cells expressed neurotransmitter receptors, and their exposure to acetylcholine impaired function. Based on these findings, we hypothesize that the physical proximity of ischemic neurons and NK cells in the CNS, as well as different neuronal signals received by NK cells within the CNS and the peripheral lymphoid organs, underlie the differential mechanisms responsible for NK cell deficiency in the periphery and in the brain. This would lead to NK cell-associated immune deficiency that favors the development of infection and post-stroke complications. To test this hypothesis, we will analyze the pathways that lead to NK cell deficiency in stroke, and relate those findings to clinical outcomes. The specific aims are: 1) To define the temporal events associated with functional changes in NK cells from competency to deficiency, and to identify the characteristics acquired by NK cells in the periphery and in the CNS after brain ischemia; 2) To identify the mechanisms responsible for NK cell deficiency in the periphery and in the CNS after brain ischemia; 3) To investigate the clinical relevance of NK cell deficiency on infection in stroke, and to test strategies of manipulation of NK cell deficiency for the reduction of post-stroke infection. In all, this proposa will advance the understanding of key neuroimmune interactions that might allow design of strategies of NK cell-based intervention as a new tool limiting risks of post-stroke infection.

描述（应用程序提供）：中枢神经系统（CNS） - 灌输淋巴细胞有助于缺血性中风中脑梗塞的进展。反过来，受损的大脑会对免疫系统施加抑制作用。尚未定义这种相互相互作用之间这种相互作用的临时关系，因此免疫介入以极大地限制脑损伤。此外，中风患者感染的高患病率需要更好地了解中风如何系统地和大脑内部的免疫调查，以打击与免疫相关的中风后并发症。我们最近表明，天然杀手（NK）细胞（先天免疫系统的关键组成部分）基本上在中风患者尸检的脑切片侧面区域中代表。在脑缺血的小鼠模型中，我们表明缺血性神经衍生的分子碱募集了NK细胞，这可能会在缺血性中风的急性阶段加速脑梗塞。随后，NK细胞暴露了频率下降和功能损害。那些NK细胞表达神经递质接收器，并暴露于乙酰胆碱受损功能。基于这些发现，我们假设CNS中缺血性神经元和NK细胞的物理近端以及NK细胞在中枢神经系统和外围淋巴机构内收到的不同神经元信号，是负责NK细胞缺乏型NK细胞缺乏症的基础。这将导致NK细胞相关的免疫缺陷，有利于感染和中风后并发症的发展。为了检验这一假设，我们将分析导致中风中NK细胞缺乏的途径，并将这些发现与临床结果相关联。具体目的是：1）定义与NK细胞在功能上的功能变化相关的临时事件，并确定NK细胞在周围和CNS中获得的特征，脑缺血之后； 2）确定导致外周和中枢神经系统缺血后NK细胞缺乏症的机制； 3）研究NK细胞缺乏症对中风中感染的临床相关性，并测试操纵NK细胞缺乏症的策略，以减少冲程后感染。总的来说，该提案将提高对关键神经免疫相互作用的理解，这可能允许设计基于NK细胞的干预策略，作为限制冲程后感染风险的新工具。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A TSPO ligand attenuates brain injury after intracerebral hemorrhage.

TSPO配体减轻脑出血后的脑损伤

DOI：
10.1096/fj.201601377rr
发表时间：
2017-08
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Li M;Ren H;Sheth KN;Shi FD;Liu Q
通讯作者：
Liu Q

Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.

器官和细胞特异性免疫反应与脑出血的结果相关

DOI：
10.1096/fj.201700324r
发表时间：
2018-01
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Zhang J;Shi K;Li Z;Li M;Han Y;Wang L;Zhang Z;Yu C;Zhang F;Song L;Dong JF;La Cava A;Sheth KN;Shi FD
通讯作者：
Shi FD

Stroke-induced immunosuppression and poststroke infection.

DOI：
10.1136/svn-2017-000123
发表时间：
2018-03
期刊：
Stroke and vascular neurology
影响因子：
5.9
作者：
Shi K;Wood K;Shi FD;Wang X;Liu Q
通讯作者：
Liu Q

Depletion of microglia augments the dopaminergic neurotoxicity of MPTP.

小胶质细胞的消耗增强了 MPTP 的多巴胺能神经毒性。

DOI：
10.1096/fj.201700833rr
发表时间：
2018-06
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Yang X;Ren H;Wood K;Li M;Qiu S;Shi FD;Ma C;Liu Q
通讯作者：
Liu Q

Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models.

大脑中动脉闭塞和光血栓性脑卒中模型晚期脑缺血时淋巴细胞的浸润和持续性