ZFP384 Inhibition Improves Microglial Function to Promote Greater Regeneration Following Stroke
Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. Both cell types are deeply involved in the intricate processes of tissue maintenance and regeneration. The central nervous system has only limited regenerative capacity, but it can regain some lost function following injury, such as that caused by a stroke. Researchers here find a way to improve the regenerative activities of microglia, and demonstrate that this intervention can improve outcomes following stroke in animal models.
After a stroke, the brain launches a coordinated repair program that involves several types of cells. Among these, microglia, the brain's resident immune cells, play a pivotal role. Immediately after an injury, microglia are activated to trigger inflammation, but thereafter, they rapidly transition into a reparative state and produce growth factors, such as insulin-like growth factor 1 (IGF1), which support remyelination, strengthen neural connections, and promote functional recovery. But this only lasts for two months, limiting the brain's capacity to repair further.
To uncover the molecular mechanism responsible for diminishing microglial reparative functions the researchers identified a specific transcription factor called ZFP384, which increases as the brain's spontaneous repair functions diminish. They discovered that ZFP384 diminished the expression of genes associated with microglial reparative functions. Mechanistically, ZFP384 disrupts the chromatin interactions mediated by the protein YY1 that are necessary for the gene expression associated with neural repair. As a result, the microglia lose their reparative properties despite the brain's ongoing recovery needs.
To investigate whether preventing this loss of reparative properties in microglia could help improve recovery, the team first genetically deleted the Zfp384 gene specifically from microglia in mouse models of stroke. Interestingly, these animals maintained their recovery-associated gene expression for a much longer period than normal mice. Sustaining the reparative state of microglia enhanced remyelination of damaged nerve fibers and promoted synaptic plasticity, resulting in significantly better long-term neurological function.
Based on these findings, the researchers developed a therapeutic antisense oligonucleotide (ASO), a short, synthetic strand of nucleic acids that specifically decreases expression of a targeted gene. ASO-Zfp384 was designed to suppress Zfp384 expression. Remarkably, the treatment sustained microglial reparative functions and remained therapeutic even when administered 1 week or 1 month after stroke onset. Rather than simply reducing inflammation, the ASO-Zfp384 helped retain the brain's own reparative program, enhancing post-stroke recovery from neurological deficits.