Emerging evidence implicates a pivotal role of cerebral inflammation in the pathophysiology of traumatic brain injury (TBI). Following TBI, microglia/macrophages may assume distinct pro-inflammatory or inflammation- resolving phenotypes, which potentiate brain injury or facilitate brain repair, respectively. The intracellular molecular switches that determine microglial/macrophage functional phenotypes after TBI are poorly understood. Identifying such molecular mechanisms may reveal novel targets to tune microglia/macrophages toward the reparative inflammation-resolving phenotype and improve long-term TBI outcomes. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from histone and non-histone proteins, thereby regulating not only gene transcription but also the activity of various proteins through post-translational modifications. Previous studies by us and others demonstrate that pan-inhibitors of Class I HDACs (HDAC1, 2, 3, 8) mitigate brain inflammation and improve neurological functions after TBI. However, it is imperative to elucidate the role of different HDAC subtypes, in order to focus on specific therapeutic targets without disrupting the beneficial functions of some HDACs in post-injury brain repair. To date, the HDAC subtype responsible for protection against TBI is unknown. It is also not known if the cellular/molecular mechanisms underlying HDAC inhibitor-afforded protection involve the alteration of microglial/macrophage phenotype. Our pilot studies show for the first time that: 1) Microglia/macrophage-specific knockout (mKO) of HDAC3, but not HDAC1 or HDAC2, improves neurobehavioral outcomes after TBI. 2) HDAC3 mKO improves gray and white matter integrity, and mitigates neuroinflammation after TBI. 4) HDAC3 inhibition ameliorates pro- inflammatory microglia-mediated neurotoxicity after neuronal stretch injury (NSI), an in vitro TBI model. 5) HDAC3 inhibition reduces the activation of signal transducer and activator of transcription 1 (STAT1), a key molecule that mediates pro-inflammatory responses in microglia/macrophages. 6) Subcutaneous delivery of RGFP966, a brain-penetrant, potent, and specific HDAC3 inhibitor, ameliorates inflammation and sensorimotor deficits after TBI. Given these observations, we propose three specific aims to test the novel hypothesis that genetic or pharmacological ablation of HDAC3 provides neuroprotection and improves brain repair and long-term outcomes after TBI by promoting inflammation-resolving microglial/macrophage responses.
Aim 1 : Test if HDAC3 mKO improves gray and white matter integrity and long-term neurological functions after TBI. Controlled cortical impact (CCI) will be induced in mice of both sexes with tamoxifen-inducible HDAC3 knockout in microglia/macrophages.
Aim 2 : Test if genetic knockout of the HDAC3-STAT1 signaling pathway shifts microglia/macrophages toward the beneficial and inflammation-resolving phenotype after TBI.
Aim 3 : Test the therapeutic potential of the specific HDAC3 inhibitor RGFP966 in resolution of inflammation and improvement of long-term TBI outcomes in young adult and aged mice of both genders.
Microglia/macrophages rapidly assume dualistic functional states after traumatic brain injury (TBI) and regulates neuroinflammation, injury progression, and brain repair. This proposal will investigate the role of histone deacetylase 3 (HDAC3) in regulating microglial phenotype and long-term TBI outcome, and the underlying mechanisms involving neuroprotection, inflammation resolution and neurorestoration. Positive results from this proposal may also pave the road for the potential clinical use of HDAC3 inhibitors as a restorative therapy to enhance rehabilitation and recovery, and improve the quality of life of TBI victims.
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