title: 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.
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Guohua
authors.initials: G
authors.lastname: Wang
authors.affiliation: Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282; and.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Hongjian
authors.initials: H
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China;
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China;
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China;
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 michael.bennett@einstein.yu.edu chenj2@upmc.edu.
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261; michael.bennett@einstein.yu.edu chenj2@upmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018920:Coculture Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006898:Hydroxylamines / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D066127:White Matter / Q000293:injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D011804:Quinolines; C410733:scriptaid; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: inflammation; microglial polarization; myelination; oligodendrocyte; traumatic brain injury