HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Abstract

Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/ macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.T raumatic brain injury (TBI) often leads to catastrophic neurological disabilities and sometimes ends in death (1). TBI results not only in gray matter damage, but also in severe white matter injury (WMI), thereby disrupting signal transmission and eliciting poor functional outcomes (2, 3). WMI in TBI patients is strongly correlated with neurological deficits, and diffusion tensor imaging of white matter offers prognostic value for neurological status (2-4). At present, there are no satisfactory therapies to protect TBI patients against either gray matter injury or WMI. Furthermore, most preclinical TBI studies greatly emphasize gray matter over white matter, which may contribute to the many disappointing results in clinical trials to date (5).Previous studies have shown that histone deacetylase (HDAC) inhibitors mitigate WMI after ischemia (6, 7). HDACs allow DNA to be wrapped more tightly around histones, thereby blocking gene transcription and acting in opposition to histone acetyltransferases that promote gene transcription (8, 9). Some HDAC inhibitors preferentially promote the transcription of neuroprotective genes. We...

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