Cell-Type-Specific Interleukin 1Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities

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. Liu et al. employ a genetic knockin reporter system in mice to track and reciprocally delete and/or express IL-1 receptor 1 (IL-1R1) in specific CNS cell types. They define cell-type-specific roles for IL-1 signaling, including an essential role for endothelial IL-1R1 in mediating sickness behavior, and provide a foundation for the dissection of IL-1R1 signaling pathways in the pathogenesis of CNS disease.