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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.
Abstract:
Neurological symptoms after brain injury can remain as lifelong detrimental sequelae because most of the spontaneous recovery response disappears within a few months after the injury1,2. Microglia have an essential role in this process; however, the cellular and molecular mechanisms that diminish spontaneous functional recovery in the brain remain unclear. Here using cellular fate analysis, we show that reparative microglia persist in the brain after a stroke even after losing their beneficial functions. In these cells, ZFP384 is identified as a pivotal transcriptional regulator that diminishes the expression of genes associated with the recovery phase, turning them into dysfunctional microglia that lose their reparative functions. Mechanistically, ZFP384 diminishes the YY1-mediated chromatin interaction necessary to induce the expression of these genes in microglia. The use of antisense oligonucleotides that target Zfp384 can sustain the broad range of neural repair effects of microglia and enhance recovery after stroke, even in the chronic phase of ischaemic stroke. Thus, therapeutics that prevent the loss of reparative immunity-the beneficial restorative functions of immune cells-can prolong functional recovery in the brain.
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.
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