THE TRANSCRIPTION FACTOR PAX6 REGULATES MICROGLIAL ACTIVATION AND RESTRAINS NEUROINFLAMMATION

Microglia modulate neurodevelopment and maintain neural homeostasis by sensing changes in the CNS; therefore, their inflammatory responses must be tightly controlled. Uncontrolled microglial activation can disrupt myelin, compromise neural function, and accelerate neurodegenerative diseases, underscoring the need to identify regulators that resolve microglial activation. Despite the significance of PAX6 as a key transcription factor in neurogenesis, its role in microglia remains uninvestigated. We found that PAX6 was expressed in neonatal mouse microglia, declined with age, yet activation increased PAX6 expression in primary mouse microglia cultures. Supporting this, human transcriptomic datasets suggest re-induction of PAX6 in microglia under chronic neuroinflammatory conditions. This led us to hypothesize that PAX6 could restrain microglial inflammatory activation and that its loss exacerbates neuroinflammation. To test this, we generated microglia-specific Pax6-deficient mice and a PAX6-depleted human microglial cell line. Loss of PAX6 shifted microglia toward a pro-inflammatory phenotype in vitro and exacerbated the clinical severity of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (MS). To gain mechanistic insights, we used antibody-targeted chromatin profiling in both human and mouse microglia. The analysis identified PAX6 binding at promoter regions of genes linked to the prevention of prolonged inflammatory responses. Our findings identify PAX6 as a microglial transcriptional regulator of inflammatory responses and may reveal new strategies to limit neuroinflammation and protect CNS integrity in MS and other disorders with chronic neuroinflammation.