BRD4 expression in microglia supports recruitment of T cells into the CNS and exacerbates EAE
Abstract:
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-specific T cells then invade into the central nervous system (CNS), resulting in neuronal demyelination. Microglia, innate immune cells in the CNS are known to regulate various neuronal diseases. However, the role of microglia in EAE has remained elusive. BRD4 is a BET protein expressed in microglia, whether BRD4 in microglia contributes to EAE has not been determined. We show that EAE pathology was markedly reduced with microglia-specific Brd4 conditional knockout (cKO). In these mice, microglia- T cell interactions were greatly reduced, leading to the lack of T cell reactivation. Microglia specific transcriptome data showed downregulation of genes required for interaction with and reactivation of T cells in Brd4 cKO samples. In summary, BRD4 plays a critical role in regulating microglia function in normal and EAE CNS.
Summary:
This study demonstrates that in a EAE model, microglia-specific Brd4 conditional knockout mice were defective in expressing genes required for microglia- T cells interaction and those involved in neuroinflammation, and demyelination resulting in fewer CNS T cell invasion and display marked reduction in EAE pathology.
Insights
Bromodomain 4 (BRD4) in microglia is crucial for multiple sclerosis pathology in mice. Blocking BRD4 in microglia reduces neuroinflammation and demyelination by limiting T cell interactions within the central nervous system.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Microglia are innate immune cells in the central nervous system (CNS) with poorly understood roles in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis.
- Bromodomain 4 (BRD4), a BET protein, is expressed in microglia, but its specific contribution to EAE pathogenesis remains undetermined.
Purpose of the Study:
- To investigate the role of microglial BRD4 in the development of EAE.
- To determine if targeting microglial BRD4 can ameliorate EAE pathology.
Main Methods:
- Generation of microglia-specific Brd4 conditional knockout (cKO) mice.
- Induction of EAE in wild-type and Brd4 cKO mice.
- Analysis of T cell infiltration, neuroinflammation, and demyelination in the CNS.
- Transcriptomic analysis of microglia from Brd4 cKO mice.
Main Results:
- Microglia-specific Brd4 cKO significantly reduced EAE pathology, including neuroinflammation and demyelination.
- Reduced T cell invasion into the CNS was observed in Brd4 cKO mice.
- Microglia-T cell interactions and T cell reactivation were markedly diminished in Brd4 cKO mice.
- Transcriptomic data revealed downregulation of genes essential for microglia-T cell interactions and reactivation in Brd4 cKO microglia.
Conclusions:
- BRD4 in microglia plays a critical role in regulating microglial function within the CNS during EAE.
- Targeting microglial BRD4 presents a potential therapeutic strategy for multiple sclerosis.
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