Brd4 expression in CD4 T cells and in microglia promotes neuroinflammation in experimental autoimmune encephalomyelitis

Microglia are resident innate immune cells in the central nervous system (CNS) that provides anti-microbial protection but also promote neuroinflammation. BRD4 is a chromatin reader that binds to acetylated histones and directs transcription of numerous genes. However, it is unknown whether and how BRD4 regulates microglia function. We addressed the role of microglia and BRD4 in a neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. It was reported earlier that in EAE, upon initial T cell activation in the peripheral lymphoid organs, CD4 ⁺ T cells migrate to CNS and are reactivated by resident or migratory antigen presenting cells resulting in full manifestation of EAE [1, 2]. Using conditional deletion of Brd4 in CD4 T cells, we reveal that BRD4 regulates T helper cell differentiation and promotes T cell migration to CNS resulting in EAE. It remained unclear whether resident microglia are capable of reactivating migrating T cells to the CNS and if BRD4 plays a role in the process. To determine the role of microglial BRD4 in EAE, we constructed conditional knockout mice lacking Brd4 (Brd4cKO) in microglia. RNA-seq analysis showed that Brd4 deletion led to the downregulation of many microglia genes in both naive and EAE conditions. Consequently, Brd4cKO mice had markedly reduced EAE pathology, namely reduced paralysis, absence of axonal demyelination and inhibited expression of inflammatory cytokines. In vehicle treated mice (vehicle) abundant number of T cells were found to be near microglia that may lead to T cell- microglia interaction and T cell reactivation. In contrast, the number of T cells detected in the CNS of Brd4cKO mice was much fewer. This may lead to reduced T cell- microglia interaction, failure of T cells to get reactivated and hence failed to achieve full manifestation of EAE. These results demonstrate that microglia are critically involved in EAE disease progression for which BRD4 is essential. In summary, BRD4 directs transcription of genes defining microglia function. By so doing BRD4 promotes demyelination and neuroinflammation to exacerbate EAE.