Within microglia, IRF8 establishes a positive feedback loop with the transcription factor PU.1, sustaining IRF8 expression.194 Following neural injury, IRF8 activates target genes that transition microglia to reactive phenotypes, which can have protective or neurotoxic effects on the nervous system.195,196 In reactive microglia, IRF1 collaborates with IRF8 to initiate transcription of IL-1β.197 The absence of Irf8 in microglia can lead to an increase in TNF-α, mediate an increase in hippocampal nerve excitability, and drive fatal epilepsy.198. Here, IRF8 is linked to epilepsy.