Sustaining microglial reparative function enhances stroke recovery

Abstract Neurological symptoms after brain injury can remain as lifelong detrimental sequelae since most spontaneous brain recovery disappears within a few months after brain injury. Microglia play an essential role in recovery processes after brain injury; however, cellular and molecular mechanisms that diminish spontaneous brain functional recovery remain unknown. We discovered by cellular fate analysis that reparative myeloid cells remained in the post-stroke brain even after losing their reparative function. ZFP384 was identified as a pivotal transcriptional regulator that diminished recovery phase–associated gene expression in reparative myeloid cells, turning them into ruined cells which lost reparative functions. ZFP384 diminished the YY1-mediated chromatin interaction necessary for expressing recovery phase–associated genes. Antisense oligonucleotide against Zfp384 sustained the broad range of neural repair effects of myeloid cells and enhanced stroke recovery, even in the chronic phase of ischemic stroke recovery. Thus, therapeutics preventing the myeloid reparative immunity from reaching a ruined state sustains brain functional recovery.