HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

Abstract

Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.

PP4‐dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

“…However, HDAC3 systemic pharmacological inhibition did not alter the extent of the CD11b‐positive inflammatory response around the injury site after spinal contusion (Kuboyama et al , ), in line with what we found here through intrathecal administration of RGFP966 after spinal dorsal hemisection. The same authors observed that systemic administration of RGFP966 did not affect neurite outgrowth of DRG neurons at 48 hours in culture (Kuboyama et al , ). This is in contrast to our findings showing that intrathecal delivery of RGFP966 promotes DRG regenerative growth in culture.…”

“…It has also been shown that HDAC3 might control the expression of immune‐related gene targets in inflammatory models of SCI such as contusion injuries, where systemic pharmacological HDAC3 inhibition with RGFP966 was followed by improved functional recovery (Kuboyama et al , ). However, HDAC3 systemic pharmacological inhibition did not alter the extent of the CD11b‐positive inflammatory response around the injury site after spinal contusion (Kuboyama et al , ), in line with what we found here through intrathecal administration of RGFP966 after spinal dorsal hemisection. The same authors observed that systemic administration of RGFP966 did not affect neurite outgrowth of DRG neurons at 48 hours in culture (Kuboyama et al , ).…”

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

“…Primary microglia were isolated from the cerebral cortices of mice as previously described with minor modifications (Kuboyama et al, ). In brief, the cerebral cortices were dissected from ddY mice (Japan SLC, Hamamatsu, Japan) at postnatal Days 2–4, and the dura mater was removed.…”

“…Cells were seeded into 10‐cm dishes and cultured at 37°C with 10% CO 2 . After 14 days, microglial cells were isolated from mixed glial cultures with mild trypsinization (Kuboyama et al, ) and seeded into eight‐well slide at a density of 2.17 × 10 4 cells/cm 2 . To detect the effects of naringenin on polarization of normal cultured microglia and expression of Aβ degradation enzymes, cells were treated with naringenin (0.1–100 μM, Cat.…”

Epigenetic reprogramming of immune cells in injury, repair, and resolution

“…Resolution of arthritis is promoted by HDAC2's interaction with Tet2, leading to deacetylation and thus repression of the Il6 locus (82). HDAC3 inhibition also proved beneficial in spinal cord injury (136).…”