Microglial HDAC3 inhibits the migration of CD8-positive T cell in the development of EAE by restraining the expression of CCL5

Multiple sclerosis (MS) is a central nervous system disease caused by auto-immune reaction induced demyelination, however, the molecular mechanism of MS remains unclear. Previous study revealed that histone deacetylase 3 (HDAC3) is upregulated in the spinal cord of MS patient. Here, we found microglial HDAC3 was upregulated in the spinal cord from experimental autoimmune encephalomyelitis (EAE) mice, the classical model of MS. So, we aim to study the role and mechanism of microglial HDAC3 in the development of EAE. Both administration of HDAC3-specific inhibitor RGFP966 and conditional knockout of Hdac3 in microglia resulted in increased demyelination and infiltration of peripheral immune cells. RNA-sequencing analysis indicated that the spinal cord from microglial Hdac3-deficient EAE mice expressed higher levels of marker genes for CD8+ T cells, B cells and granulocytes. Immunostaining and flow cytometry furtherly confirmed that microglial Hdac3-deficiency increased the infiltration of CD8+ T cells in the spinal cord during the development of EAE. Lastly, we identified that microglia-derived C-C motif ligand 5 (CCL5) increasing might be the driver for CD8+ T cell migration in EAE development. Inhibition of HDAC3 by RGFP966, conditional knockout and siRNA, all led to increased transcription of CCL5 and more migration of CD8+ T cells. Consistently, the acetylation levels at H3K9 on the promoter of Ccl5 were upregulated in HDAC3-inhibited microglia as well. Microglial HDAC3 deficiency resulted in upregulated expression of CCL5, which promoted the migration of CD8+ T cells into the spinal cord in the development of EAE. Upregulation of HDAC3 in microglia inhibited the migration of CD8-positive T cell by restraining the expression of CCL5, which may help us understand spontaneous remission mechanism of MS and EAE.