缺血性脑损伤对免疫系统的影响：器官特异性因素和作用机制

Acute brain injury such as acute ischemic stroke (AIS) dramatically dampens immunity that facilitates occurrence of infections after stroke onset. Emergence of post-stroke infections in the lung or urinary tract often exacerbates the clinical outcome of patients with stroke. The failure of two large clinical trials of prophylaxis antibiotics highlights the need for a better understanding of mechanisms leading to immune deficiency and identification of means to combat post-stroke infections. In our previous investigations, we found that in patients with AIS, cellular immunity as reflected by natural killer (NK) cells displayed distinct phenotype and function in the peripheral lymphoid organ, spleen, and brain. These properties can be mirrored in mice subjected to middle cerebral artery (MCA) occlusion. Of interest, the alteration of NK cells was governed by neurogenic pathways initiated by the ischemic brain. However, still unknown are mechanisms leading to NK cell deficiency after stroke and to what extent it contributes to post-stroke infections. In this study, we hypothesize that specific neurogenic innervations-induced transcriptional modification of cellular immunity in the brain and periphery dictate the phenotype and function of NK cells in these two compartments; and that post-stroke infection can be limited by manipulation of transcriptional pathways in NK cells. To test this hypothesis, we will 1) comprehensively characterize the temporal and transcriptional features of NK cells in the brain and spleen after brain ischemia; 2) determine the impact of post-stroke neurogenic innervations on NK cell transcriptome and identify the key transcription factors that are necessary for the dampened NK cell response after brain ischemia; 3) determine the efficacy of manipulating individual transcription factors to combat infectious complications after brain ischemia. The results of this work will significantly advance our knowledge on determinants that dictate organ-specific immunity in the context of a major neurological disease, i.e. stroke. The outcome will establish a foundation for the design of new treatment for post-stroke infections.

急性脑损伤包括缺血性脑卒中（AIS）后免疫缺陷是造成脑卒中后感染的重要原因。AIS后并发肺炎和尿路感染直接影响其预后。近期完成的预防性抗生素的随机对照临床试验的失败，更突出了阐明卒中后免疫缺陷机制的迫切性。我们发现卒中病人中，以自然杀伤（NK）细胞为代表的细胞免疫在脑内和外周具有不同特征的功能缺失。脑卒中动物模型中，我们发现NK细胞具有类似免疫缺陷特征且在脑内和外周由不同的神经通路介导。据此，我们假设脑缺血通过特定神经通路改变了脑内和外周NK细胞的转录调控机制，导致其功能缺损；而调节NK细胞胞内信号通路能维持NK细胞活性并增强免疫防御。本研究将明确：1）脑缺血后不同阶段外周和中枢浸润NK细胞分子特征及转录调控机制变化；2）卒中后特定神经通路导致中枢和外周的NK细胞功能缺失的分子机制；3）调控NK细胞内分子通路对卒中后免疫防御的影响。本研究将为控制卒中后感染提供新策略。

急性脑损伤后免疫缺陷是造成脑卒中后感染的重要原因，而卒中后感染直接影响其预后。预防性抗生素的随机对照临床试验的失败，更突出了阐明卒中后免疫缺陷机制的迫切性。本项目以NK细胞为代表确立了以下研究目标：1）明确脑缺血后不同阶段外周和中枢浸润NK细胞分子特征及转录调控机制变化；2）卒中后特定神经通路导致中枢和外周的NK细胞功能缺失的分子机制；3）调控NK细胞内分子通路对卒中后免疫防御的影响。.经过5年的研究，课题组顺利完成预期目标。主要成果如下：1）以NK细胞为例揭示了脑卒中后免疫细胞在不同器官功能的变化和调控网络，干预特定调控通路可减轻卒中后感染风险，为临床上通过免疫干预防治卒中后感染奠定了理论基础并提出了初步方案。2）从器官特异性免疫学角度，总结现有临床和动物实验证据，提出脑卒中后全脑炎症概念，对阐明脑卒中后迟发性神经功能障碍提供了理论基础。3）阐明了NK细胞在出血性脑卒中后脑水肿发生中的机制。4）探索了NK细胞在脑衰老中对神经生发和认知功能减退的影响及作用。5）探索了免疫细胞在脑卒中溶栓后出血转化中的作用机制，接受tPA治疗的患者的血液内中性粒细胞和淋巴细胞被快速动员，并在动物模型中得到验证。免疫干预可减轻tPA诱发的出血转化。6）用单克隆抗体治疗脑特异性自身免疫病神经脊髓炎谱系疾病（NMOSD）。在托珠单抗和硫唑嘌呤头对头比较中，发现前者在减少复发次数和安全性方面有显著优势，为完善NMOSD治疗指南提供了关键临床证据。.本项目在国际期刊发表研究论文20篇，其中包括Lancet Neurology (2篇)，Immunity, Nature Neuroscience, Circulation Research, Science Translational Medicine, Annals Neurology等各1篇。申请专利5项，已授权1项。项目成果获得了天津市自然科学一等奖1项。