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

Significance Moderate or severe traumatic brain injury (TBI) damages white matter, thereby contributing to long-term neurological deficits. Currently, there are no satisfactory therapies to mitigate this white matter injury (WMI). Here we show that inhibition of histone deacetylases (HDACs) exerts robust structural and functional protection of white matter in a murine model of TBI/WMI by polarizing microglia/macrophages toward the beneficial M2 phenotype. HDAC inhibition shifted microglia/macrophage phenotype by up-regulating glycogen synthase kinase 3 beta (GSK3β), which inactivated phosphatase and tensin homologue (PTEN) through phosphorylation, thereby promoting PI3K/Akt signaling. The GSK3β-dependent M2 phenotype exerted potent anti-inflammatory effects that protected myelin-forming oligodendrocytes and diminished WMI. These results reveal a previously unexplored role for GSK3β/PTEN/PI3K signaling in the regulation of microglia/macrophages and demonstrate the promise of HDAC inhibition in the treatment of TBI/WMI.