TY - JOUR T1 - Interleukin 1 Type 1 Receptor Restore: A Genetic Mouse Model for Studying Interleukin 1 Receptor-Mediated Effects in Specific Cell Types JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2860 LP - 2870 DO - 10.1523/JNEUROSCI.3199-14.2015 VL - 35 IS - 7 AU - Xiaoyu Liu AU - Tetsuji Yamashita AU - Qun Chen AU - Natalya Belevych AU - Daniel B. Mckim AU - Andrew J. Tarr AU - Vincenzo Coppola AU - Nikitaa Nath AU - Daniel P. Nemeth AU - Zunera W. Syed AU - John F. Sheridan AU - Jonathan P. Godbout AU - Jian Zuo AU - Ning Quan Y1 - 2015/02/18 UR - http://www.jneurosci.org/content/35/7/2860.abstract N2 - Interleukin-1 (IL-1) mediates diverse neurophysiological and neuropathological effects in the CNS through type I IL-1 receptor (IL-1R1). However, identification of IL-1R1-expressing cell types and cell-type-specific functions of IL-1R1 remains challenging. In this study, we created a novel genetic mouse model in which IL-1R1 gene expression is disrupted by an intronic insertion of a loxP flanked disruptive sequence that can be deleted by Cre recombinase, resulting in restored IL-1R1 gene expression under its endogenous promoters. A second mutation was introduced at stop codon of the IL-1R1 gene to allow tracking of the restored IL-1R1 protein by a 3HA tag and IL-1R1 mRNA by tdTomato fluorescence. These animals were designated as IL-1R1r/r and exhibited an IL-1R1 knock-out phenotype. We used IL-1R1 globally restored mice (IL-1R1GR/GR) as an IL-1R1 reporter and observed concordant labeling of IL-1R1 mRNA and protein in brain endothelial cells. Two cell-type-specific IL-1R1 restore lines were generated: Tie2Cre-IL-1R1r/r and LysMCre-IL-1R1r/r. Brain endothelial COX-2 expression, CNS leukocyte infiltration, and global microglia activation induced by intracerebroventricular injection of IL-1β were not observed in IL-1R1r/r or LysMCre-IL-1R1r/r mice, but were restored in Tie2Cre-IL-1R1r/r mice. These results reveal IL-1R1 expression in endothelial cells alone is sufficient to mediate these central IL-1-induced responses. In addition, ex vivo IL-1β stimulation increased IL-1β expression in bone marrow cells in wild-type, Tie2Cre-IL-1R1r/r, and LysMCre-IL-1R1r/r, but not IL-1R1r/r mice. These results demonstrate this IL-1R1 restore model is a valuable tool for studying cell-type-specific functions of IL-1R1. ER -