Sustaining microglial reparative function enhances stroke recovery

Jun Tsuyama1,2,3, Seiichiro Sakai4,5,6, Kumiko Kurabayashi4,5,6

  • 1Department of Neuroinflammation and Repair, Medical Research Laboratory, Institute of Science Tokyo, Tokyo, Japan. tsuyama.j.662a@m.isct.ac.jp.

Nature
|May 13, 2026
PubMed

Insights

Researchers found that ZFP384 causes microglia to lose their beneficial functions after a stroke. Targeting ZFP384 can restore these functions and improve brain recovery, even long after the injury.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Neurological deficits after brain injury often persist due to diminished spontaneous recovery.
  • Microglia play a critical role in brain repair, but the mechanisms limiting recovery are not fully understood.

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms behind the loss of microglial reparative functions post-stroke.
  • To identify therapeutic targets for enhancing long-term brain functional recovery.

Main Methods:

  • Cellular fate analysis was employed to track microglial function after stroke.
  • Investigated the role of the transcriptional regulator ZFP384 in microglial dysfunction.
  • Utilized antisense oligonucleotides targeting Zfp384 in preclinical models.

Main Results:

  • Reparative microglia persist post-stroke but lose beneficial functions.
  • ZFP384 was identified as a key regulator diminishing reparative gene expression in microglia.
  • ZFP384 inhibits YY1-mediated chromatin interactions essential for repair gene induction.
  • Targeting Zfp384 with antisense oligonucleotides sustained microglial repair functions and improved chronic stroke recovery.

Conclusions:

  • ZFP384-mediated microglial dysfunction contributes to limited functional recovery after stroke.
  • Therapeutic strategies targeting ZFP384 can restore microglial reparative immunity and promote prolonged brain repair.
  • Preventing the loss of immune cell restorative functions offers a promising approach for enhancing neurological recovery.