Stroke induced-NK cell deficiency: mechanisms and clinical implications

 描述（由申请方提供）：中枢神经系统（CNS）浸润淋巴细胞有助于缺血性卒中中脑梗死的进展。受损的大脑反过来会对免疫系统产生抑制作用。免疫系统和缺血性脑之间的这种相互作用的时间关系尚未确定，使得免疫干预限制脑损伤非常困难。此外，中风患者感染的高患病率需要更好地了解中风如何影响全身和大脑内的免疫反应，以对抗免疫相关的中风后并发症。我们最近发现，自然杀伤（NK）细胞-先天免疫系统的关键组成部分-在中风患者尸检的脑切片的梗死周围区域中大量存在。在小鼠脑缺血模型中，我们发现缺血性神经元衍生的fractalkine募集NK细胞，这可以加速缺血性中风急性期的脑梗死。随后，NK细胞表现出频率降低和功能受损。这些NK细胞表达神经递质受体，它们暴露于乙酰胆碱会损害功能。基于这些研究结果，我们假设，物理接近的缺血神经元和NK细胞在中枢神经系统，以及不同的神经元信号接收的NK细胞在中枢神经系统和外周淋巴器官，背后的差异机制负责NK细胞缺乏症在外周和大脑。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。为了验证这一假设，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联系起来。具体目标是：1）明确脑缺血后NK细胞功能从胜任到缺乏的时间过程，以及脑缺血后外周和中枢神经系统NK细胞获得的特征; 2）明确脑缺血后外周和中枢神经系统NK细胞缺乏的机制;（3）探讨NK细胞缺陷与脑卒中后感染的临床相关性，并探讨干预NK细胞缺陷以减少脑卒中后感染的策略。总之，这一提议将促进对关键神经免疫相互作用的理解，这可能允许设计基于NK细胞的干预策略，作为限制中风后感染风险的新工具。

 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.