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Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke

Yue Zhang1, Jiaying Li1, Yongfang Zhao1

  • 1Department of Critical Care Medicine of Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China.

Science Advances
|March 6, 2024
PubMed

Insights

Histone deacetylase 3 (HDAC3) inhibition in microglia improves outcomes after ischemic stroke by reducing harmful inflammation. This occurs by blocking the proliferation of pro-inflammatory microglia via the PU.1 pathway.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Microglial polarization and accumulation in the penumbra are key to neuroinflammation post-ischemic stroke, causing neuronal damage.
  • Histone deacetylase 3 (HDAC3) regulates inflammation and cell proliferation, but its specific role in microgliosis and polarization after stroke is unknown.

Purpose of the Study:

  • To investigate the role of HDAC3 in microglial polarization and its impact on ischemic stroke pathophysiology.
  • To elucidate the molecular mechanisms by which HDAC3 influences microglial responses and stroke outcomes.

Main Methods:

  • Generated microglial-specific HDAC3 knockout (HDAC3-miKO) mice.
  • Performed RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) on microglia post-stroke.
  • Utilized adeno-associated virus (AAV) to overexpress PU.1 in microglia.

Main Results:

  • HDAC3-miKO significantly improved long-term functional and histological outcomes after ischemic stroke.
  • HDAC3 deficiency in microglia primarily affected mitotic processes, specifically inhibiting the proliferation of pro-inflammatory microglia.
  • HDAC3-miKO altered chromatin accessibility at PU.1 motifs, and PU.1 overexpression reversed the protective effects of HDAC3-miKO.

Conclusions:

  • The HDAC3/PU.1 axis plays a critical role in regulating microglial proliferation and polarization post-stroke.
  • Targeting HDAC3 in microglia offers a potential therapeutic strategy to mitigate neuroinflammation and improve recovery after ischemic stroke.

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