73. Cell type-specific interleukin-1 receptor 1 mediates distinct downstream effects in the central nervous system following an intracerebralventricular injection of interleukin-1 beta

Abstract

Interleukin-1 (IL-1) in the brain can contribute to numerous behavior abnormalities. Previous studies have shown that IL-1 exerts distinct actions on different cell types with the same IL-1 receptor (IL-1R1) resulting in the activation of different signaling pathways. Additionally, the roles of neuronal and endothelial IL-1R1 expression in mediating IL-1 induced illness behavior and learning and memory deficits remain controversial due to the lack of animal models to precisely dissect a specific cell type from the brain. In this study, we created a novel genetic mouse model that selectively restores functional IL-1R1 on defined cell types under its endogenous promoters. In the IL-1R1 restore mice (R1r/r), the normal IL-1R1 expression are disrupted. After they mated with Tie2Cre or LysMCre mice, IL-1R1 expression has been shown to be restored in endothelial cells or myeloid cells with its mRNA tracked by Tdtomato fluorescence and protein expression monitored by 3HA tag immunohistochemistry. Activation of cyclooxygenase 2 and infiltration of CD45+ cells into the brain parenchyma following an intracerebralventriclar IL-1β injection were observed in the Tie2Cre R1r/r mice, the same as in the wild type control, but not R1r/r mice. The LysMCre R1r/r mice showed distinct responses to IL-1β injection from Tie2Cre, indicating IL-1R1 on different cell types mediate different effects. Additional studies will further distinguish the cellular signaling pathways triggered by IL-1R1 in endothelial cells versus myeloid cells.