Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA.
Immunity. 2019 Feb 19;50(2):317-333.e6. doi: 10.1016/j.immuni.2018.12.012. Epub 2019 Jan 22.
Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.
白细胞介素-1（IL-1）信号对于中枢神经系统（CNS）中多种潜在致病过程很重要，但 IL-1 信号的细胞类型特异性作用尚不清楚。我们使用小鼠中的一种遗传基因敲入报告系统来追踪并在特定细胞类型（包括内皮细胞、心室细胞、外周髓样细胞、小胶质细胞、星形胶质细胞和神经元）中进行 IL-1 受体 1（IL-1R1）的反向缺失或表达。我们发现内皮细胞中的 IL-1R1 对于介导疾病行为以及驱动白细胞向 CNS 的募集和神经发生受损是必要且充分的，而心室中的 IL-1R1 对于单核细胞向 CNS 的募集至关重要。尽管小胶质细胞不表达 IL-1R1，但内皮细胞中的 IL-1 刺激导致小胶质细胞中 IL-1 的诱导。总之，这些发现描述了大脑中表达 IL-1R1 的系统的结构和功能，并为 CNS 疾病发病机制中 IL-1R1 信号通路的剖析和鉴定奠定了基础。
