Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 9, Pages 2853-2858Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1501441112
Keywords
traumatic brain injury; oligodendrocyte; microglial polarization; myelination; inflammation
Categories
Funding
- National Institutes of Health [NS36736, NS43802, NS45048, NS45287]
- US Department of Veterans Affairs Research Career Scientist Award
- Chinese Natural Science Foundation [81020108021, 81171149, 81371306, 81000497, 81471257, 81228008]
- PhD Training Grant [20120071110042]
- Ministry of Education of the People's Republic of China Talent Training Fellowship Grant [J1210041]
- State Administration of Foreign Experts Affairs High-End Distinguished Professorship Grant [GDW20133100069]
- Hillman Foundation Award
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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 (GSK3 beta), 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 GSK3 beta 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 GSK3 beta may be more subtle than previously thought, in that GSK3 beta 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.
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