小胶质细胞分泌的CD52抑制炎症向中枢转移的机制

Infection is the leading cause of mortality among children under five-years-old. Early systemic infection can affect neurodevelopment in the long term, and combined with a second hit can increase the risk of disorders related to neurological abnormalities such as schizophrenia, autism, and Alzheimer's syndrome. Neuroinflammation and microglia activation caused by infection may be a common mechanism of these neurological diseases. Recent studies have also indicated that immune memory induced by early infection can affect the development of Alzheimer's disease, but the cellular and molecular mechanisms of immune memory have not been found. Recent studies by the applicant have shown that early systemic infection can induce immunosuppression, a form of immune memory, in the central nervous system, and induce high-level expression of CD52 in microglia and macrophages. Here, we propose to use a combination of in situ hybridization, single cell RNA sequencing, pharmacology, electrophysiology, immunohistochemistry, quantitative morphological analysis to identify the mechanism of immunosuppression mediated by microglia in the nervous system and its influence on neural development. The results of these investigations will deepen our understanding of the relationship between infection and neurological diseases, and provide new insight into the prevention and treatment of several neurological diseases.

感染是五岁以下儿童致死的主要原因。早期系统性感染可长远地影响神经发育，结合第二次打击可增加患精神分裂症、自闭症等神经系统异常相关疾病的风险。由感染引起的神经炎症和小胶质细胞激活可能是导致这些神经疾病的共同机制。近期研究也表明，早期感染引起的免疫记忆可以影响阿兹海默综合症的疾病发展，但并没有找到免疫记忆的细胞和分子机制。申请人近期研究发现，早期系统性感染可以诱导中枢神经系统产生免疫抑制——一种免疫记忆形式，并且诱导小胶质细胞和巨噬细胞特异性地高表达CD52。本项目拟本项目拟结合原位杂交、单细胞RNA测序、药理学、电生理学、免疫组织化学、定量形态学分析等手段系统性地阐述小胶质细胞介导神经系统免疫抑制的机制及其对神经发育的影响。本项目将对深入理解感染与神经疾病的关系有重要的理论指导意义，并为某些神经疾病的预防和治疗提供新的思路。

感染是五岁以下儿童致死的主要原因。早期系统性感染可长远地影响神经发育，结合第二次打击可增加患精神分裂症、自闭症等神经系统异常相关疾病的风险，但其细胞和分子机制还不明确。我们的研究首次采用单细胞测序等技术证明早期炎症可引起脑内八种主要的免疫反应细胞产生免疫抑制现象，在经历第二次打击时炎症反应减弱，细胞因子的产生、NF-kB信号通路、吞噬等炎症相关信号均受到广泛地抑制。小胶质细胞和血管旁巨噬细胞的免疫抑制程度低于其他六种细胞，炎症相关通路仍可被显著激活。更有趣地是，早期炎症并未抑制氧化磷酸化通路在这两种细胞中的激活。并且，免疫组化染色证明早期炎症可激发脑内小胶质细胞和巨噬细胞的长期激活，在接受二次打击后小胶质细胞可进一步激活。以上研究说明，早期炎症引起小胶质细胞和巨噬细胞的长期激活、以及二次打击后氧化磷酸化水平升高可能是二次打击促进神经类疾病发展的关键原因。本项目对深入理解感染与神经疾病的关系具有重要的意义，并可能为神经类疾病的预防提供新的思路。