Discussion
Here, we have identified cell type-specific IL-1R1 mediated mechanisms, which may contribute to the neuroprotection observed in LPS preconditioning. These findings identify key cellular and molecular contributors in LPS-induced neuroprotection.
Methods
Using our IL-1R1 restore genetic mouse model, mouse lines were generated to restrict IL-1R1 expression either to endothelia (Tie2-Cre-Il1r1r/r) or microglia (Cx3Cr1-Cre-Il1r1 r/r), in addition to either global ablation (Il1r1 r/r) or global restoration of IL-1R1 (Il1r1 GR/GR). The LPS preconditioning paradigm consisted of four daily i.p. injections of LPS at 1 mg/kg (4d LPS). 24 hrs following the final i.p. LPS injection, tissue was collected for qPCR analysis, immunohistochemistry, or FAC sorting.
Results
Following 4d LPS, we found multiple phenotypes that are dependent on IL-1R1 signaling such as microglia morphology alterations, increased microglial M2-like gene expression, and clustering of microglia onto the brain vasculature. We determined that 4d LPS induces microglial morphological changes, clustering at the vasculature, and gene expression changes are dependent on endothelial IL-1R1, but not microglial IL-1R1. A novel observation was the induction of microglial IL-1R1 (mIL-1R1) following 4d LPS. The induced mIL-1R1 permits a unique response to central IL-1β: the mIL-1R1 dependent induction of IL-1R1 antagonist (IL-1RA) and IL-1β gene expression. Analysis of RNA sequencing datasets revealed that mIL-1R1 is also induced in neurodegenerative diseases.