Brain endothelial IL-1R1 mediates central IL-1 induced neuroinflammation and anxiety-like behavior

Abstract

Interleukin-1 (IL-1) mediates diverse neuropathological effects and behavioral changes in the central nervous system (CNS) through type I IL-1 receptor (IL-1R1). Different CNS cell types are known to mediate different IL-1 effects. In this study, we investigated IL-1 induced neuroinflammation and anxiety using three cell-type specific IL-1R1 expressing mouse lines: Tie2Cre-IL-1R1r/r (IL-1R1 restricted to endothelial cells and hematopoietic cells), LysMCre-IL-1R1r/r (myeloid cells) or HipAAV2Cre-IL-1R1r/r (hippocampal neurons). Following intracerebroventricular (ICV) IL-1 injection microglial activation was induced in all three mouse lines but with distinct morphological characteristics. Microglia in Tie2Cre-IL-1R1r/r mice developed most abundant branches and longest processes length. Cytokine expression analysis showed microglia in wild-type (WT) and Tie2Cre-IL-1R1r/r mice upregulated proinflammatory cytokines IL-1 β and TNF- α , which did not occur in LysMCre-IL-1R1 and AAVCre-IL-1R1 mice which lacked endothelial IL-1R1. We then adoptively transferred SVEC4-10 cells, an IL-1R1 expressing endothelial cell line, into striatum of IL-1R1 knockout mice (IL-1R1r/r). After the transfer, microglial activation was induced by ICV IL-1 but not by saline, indicating endothelial IL-1R1 is sufficient to mediate inflammatory microglial activation. Furthermore, we found endothelial IL-1R1 dependent microglial activation was mediated via exocytosis of danger signals such as ATP. In addition, anxiety-like behavior developed in WT and Tie2Cre-IL-1R1r/r mice but not LysMCre-IL-1R1r/r or AAV2Cre-IL-1R1r/r lines. Collectively, these findings demonstrate that brain endothelial IL-1R1 mediates central IL-1 induced neuroinflammation and anxiety-like behavior.