Brd4 expression in microglia supports microglial activation, T cell recruitment, and demyelination in EAE

In EAE, a mouse model of multiple sclerosis, immunization with MOG autoantigen results in the generation of Th1/Th17 T cells in the periphery. MOG antigen-specific T cells then invade into the central nervous system (CNS) resulting in neuronal demyelination. Microglia, specialized innate immune cells in the CNS, have been suggested to participate in the pathogenesis of EAE. Bromodomain inhibitors have been reported to reduce EAE pathology by inhibiting T cells. However, the contribution of BRD4 in EAE pathology is unknown. In this study, we demonstrate that microglia-specific Brd4 conditional knockout (cKO) mice, displayed markedly reduced EAE pathology. Brd4cKO microglia failed to express inflammation and activation-related genes and had reduced CNS T cell invasion. Moreover, Brd4cKO microglia: invading T cell interactions were markedly reduced, suggesting that Brd4-dependent microglial genes may play important roles in facilitating T cell restimulation within the CNS. In summary, our results demonstrate a model in which microglial BRD4 plays a key role in supporting neuroinflammation in EAE. Overall design: To investigate the role of BRD4 in EAE pathogenesis, we generared Tamoxifen inducible Brd4 KO mice to delete Brd4 in microglia. To induce EAE mice were immunized with MOG. CNS mononuclear cells were isolated from both immunized and naïve mice. Microglia were purified using FACS/Aria. We performed gene expression profiling from RNA-seq data obtained from four WT and four KO samples each from EAE and naïve mice.