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

• 批准号: 9107131
• 负责人: FU-DONG SHI
• 金额: $ 37.89万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107131
• 关键词: Acetylcholine; Acute; Adoptive Transfer; Adrenergic Agents; Adrenergic Antagonists; Area; Autopsy; Bacterial Infections; Brain; Brain Infarction; Brain Injuries; Brain Ischemia; Cause of Death; Cells; Cerebral Infarction; Cerebral Ischemia; Characteristics; Clinical; Cytolysis; Cytometry; Development; Event; Exhibits; Exposure to; Fractalkine; Frequencies; Genetic; High Prevalence; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Deficiency Syndromes; Immunosuppression; Individual; Infarction; Infection; Infiltration; Inflammation; Inflammatory Response; 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 Trauma; Nervous System control; Nervous system structure; Neuraxis; Neurons; Neurotransmitter Receptor; Nicotinic Receptors; Organ; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Process; Recruitment Activity; Risk; Role; Signal Transduction; Spleen; Staging; 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; improved; interest; killer T cell; liver function; mortality; mouse model; neuroregulation; neurotransmission; novel strategies; pathogen; post stroke; public health relevance; tool

 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(由申请人提供)：中枢神经系统(CNS)-浸润性淋巴细胞有助于缺血性卒中脑梗塞的进展。受损的大脑反过来会对免疫系统产生抑制作用。免疫系统和脑缺血之间这种相互作用的时间关系尚未确定，这使得免疫干预限制脑损伤变得极其困难。此外，中风患者的高感染率需要更好地了解中风如何影响系统和大脑内的免疫反应，以对抗与免疫相关的中风后并发症。我们最近发现，自然杀伤(NK)细胞--天然免疫系统的关键组成部分--在中风患者尸检的脑梗塞周围区域大量表达。在脑缺血的小鼠模型中，我们发现缺血神经元衍生的Fractalkine募集了NK细胞，这可以加速缺血性中风急性期的脑梗塞。随后，NK细胞频率降低，功能受损。这些NK细胞表达神经递质受体，暴露于乙酰胆碱会损害其功能。基于这些发现，我们推测，中枢神经系统中缺血神经元和NK细胞的物理接近，以及中枢神经系统和外周淋巴器官中NK细胞接收的不同神经元信号，是导致外周和脑内NK细胞缺陷的不同机制。这将导致NK细胞相关的免疫缺陷，从而有利于感染和中风后并发症的发展。为了验证这一假设，我们将分析导致中风患者NK细胞缺陷的途径，并将这些发现与临床结果联系起来。其具体目的是：1)确定与NK细胞功能从有能力转变为缺乏功能相关的时间事件，并确定脑缺血后外周和中枢NK细胞获得的特征；2)确定脑缺血后外周和中枢NK细胞缺乏的机制；3)探讨NK细胞缺乏与卒中感染的临床相关性，并测试NK细胞缺乏的操作策略，以减少卒中后感染。总而言之，这一提议将促进对关键神经免疫相互作用的理解，这可能有助于设计基于NK细胞的干预策略，作为限制卒中后感染风险的新工具。