美国加州大学旧金山分校Katerina Akassoglou及其课题组通过多组学分析，确定了血液诱导的小胶质细胞在神经变性过程中的功能。2023年6月8日出版的《自然—免疫学》发表了这项成果。

研究人员建立了一个无偏倚的血液先天免疫多组学和遗传功能丧失通路，以确定血液诱导的先天免疫极化转录组和磷酸化蛋白质组及其在小胶质细胞神经毒性中的作用。血液诱导广泛的小胶质细胞转录变化，包括与氧化应激和神经退行性疾病相关基因的变化。多功能比较组学表明，血液蛋白在小胶质细胞和巨噬细胞中诱导不同受体介导的转录程序，例如氧化还原、I型干扰素和淋巴细胞招募。凝血因子纤维蛋白原缺失在很大程度上逆转了血液诱导小胶质细胞的神经退行性特征。

利用遗传方法破坏阿尔茨海默病小鼠中纤维蛋白原与CD11b的结合减少了小胶质细胞脂质代谢和神经退行性特征，这些特征与多发性硬化症小鼠自身免疫诱导的神经炎症共享。该数据为研究血液蛋白免疫学提供了一个交互式资源，其为通过免疫和血管信号对小胶质细胞激活的治疗策略提供支持。

据介绍，通过破坏血脑屏障和先天免疫激活的血液蛋白外渗是神经系统疾病的标志和新兴的治疗靶点。然而，血液蛋白如何使先天免疫细胞极化是未知的。

附：英文原文

Title: Defining blood-induced microglia functions in neurodegeneration through multiomic profiling

Author: Mendiola, Andrew S., Yan, Zhaoqi, Dixit, Karuna, Johnson, Jeffrey R., Bouhaddou, Mehdi, Meyer-Franke, Anke, Shin, Min-Gyoung, Yong, Yu, Agrawal, Ayushi, MacDonald, Eilidh, Muthukumar, Gayathri, Pearce, Clairice, Arun, Nikhita, Cabriga, Belinda, Meza-Acevedo, Rosa, Alzamora, Maria del Pilar S., Zamvil, Scott S., Pico, Alexander R., Ryu, Jae Kyu, Krogan, Nevan J., Akassoglou, Katerina

Issue&Volume: 2023-06-08

Abstract: Blood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer’s disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

DOI: 10.1038/s41590-023-01522-0

Source: https://www.nature.com/articles/s41590-023-01522-0