Attraction and role of innate immune cells in brain injury

脑损伤是中风后造成的，许多患者在中风后出现了修复不良的脑损伤。趋化因子CXCL12与包括脑在内的受损组织的重组有关。它在脑血管内皮细胞中表达，并在脑损伤区域内显著上调。尽管许多表达CXCL12受体CXCR4的免疫细胞被脑病变吸引，但脑CXCL12与免疫细胞募集之间的因果关系尚未确定。在这里，我们关注表达CXCR4的先天免疫细胞，即先天淋巴样细胞（ILCs）和骨髓源性巨噬细胞（BMdM）。ilc是最近才被发现的，人们对它们在脑损伤中的作用知之甚少。此外，BMdM在受损大脑中的特异性功能仍不清楚，因为几乎不可能将它们与反应性小胶质细胞区分开来。我们生成了一种新的细胞命运定位策略，使我们能够在不标记驻留小胶质细胞的情况下特异性地识别入侵的BMdM。此外，我们建立了几种基因小鼠模型来干扰感兴趣的细胞群中的CXCL12/CXCR4通路。有了这些独特的工具，我们将能够研究先天免疫细胞募集的时空模式，先天免疫细胞的相互作用以及CXCL12在局灶性脑缺血模型损伤和功能恢复中的作用。该项目将为中风期间的基本免疫过程提供新的见解，以便在未来集中治疗。

Brain injury is inflicted after stroke and many patients suffer from ill-repaired brain lesions after this event. Chemokine CXCL12 has been implicated in reorganization of damaged tissues including brain. It is expressed in cerebral vascular endothelial cells and is dramatically upregulated within the region of a brain injury. Although many immune cells expressing the CXCL12 receptor CXCR4 are attracted towards brain lesions, a causal relationship between cerebral CXCL12 and immune cell recruitment has not been established. Here, we focus on innate immune cells expressing CXCR4, namely innate lymphoid cells (ILCs) and bone marrow-derived macrophages (BMdM). ILCs have been discovered only recently, and very little is known about their role in brain injury. Also, the function of BMdM specifically in the lesioned brain is still unclear since it is almost impossible to distinguish them from reactive microglia. We generated a novel cell fate mapping strategy which enables us to identify specifically invading BMdM without labelling resident microglia. In addition, we established several genetic mouse models to interfere with the CXCL12/CXCR4 pathway in cell populations of interest. With these unique tools, we will be able to study spatial and temporal patterns of innate immune cell recruitment, interaction of innate immune cells and the role of CXCL12 in damage and functional recovery in established models of focal cerebral ischemia. This project will provide new insights into the fundamental immune processes during stroke in order to focus treatments in the future.