Abstract # 1736 The role of endothelial IL-1R1 in anxiogenic neuroinflammation

We have demonstrated previously that cell-type specific IL-1R1 mediates diverse functions of interleukin 1 (IL-1) in the CNS. A specific IL-1R1 expressing cell type which mediates IL-1-induced neuroinflammation and anxiety-like behavior has yet to be identified. In the current study, we investigated the responses to IL-1 in multiple mouse lines in which IL-1R1 was selectively expressed in endothelial and hematopoietic cells (Tie2Cre-IL-1R1r/r), myeloid cells (LysMCre-IL-1R1r/r), microglial cells (CX3CR1Cre-IL-1R1r/r) or location-specific neurons (AAV2Cre-IL-1R1r/r). Acute intracerebroventricular (ICV) injections of IL-1 in these lines induced anxiety-like behavior in the wild type (WT) and Tie2Cre-IL-1R1r/r mice, but not in other mouse lines. ICV IL-1 injections in the WT mice also induced an increase of proinflammatory cytokines IL-1 and TNF, leukocyte infiltration as well as microglial cell activation with Iba-1-labeled elongated processes and increased branches, which were also found in the Tie2Cre-IL-1R1r/r mice but not in other mouse lines. To exclude the possibility that infiltrating leukocytes trigger the microglial activation, we depleted leukocytes in the Tie2Cre-IL-1R1r/r mice with vinblastine or cyclophosphamide. After the depletion, microglial activation was still detected in response to IL-1. Furthermore, in the Tie2Cre-IL-1R1r/r mice, chronic central IL-1 induced neuroinflammation, characterized by microglial activation and leukocyte infiltration. These responses were significantly enhanced by peripheral IL-1 administration. These results demonstrated that signaling through endothelial IL-1R1 from both central and peripheral IL-1 can mediate IL-1-induced anxiogenic neuroinflammation.