Intraperitoneal injection of IL-4/IFN-γ modulates the proportions of microglial phenotypes and improves epilepsy outcomes in a pilocarpine model of acquired epilepsy

Abstract Recent studies have reported microglia that are activated in the central nervous system (CNS) in patients with temporal lobe epilepsy and animal models of epilepsy. However, limited data are available on the dynamic changes of the proportions of various phenotypes of microglia throughout epileptogenesis and whether IL-4/IFN-γ administration can modulate the proportions of microglial phenotypes to affect the outcome of epilepsy. The current study examined this issue using a mouse model of pilocarpine-induced epilepsy. Flow cytometry showed that classically activated microglia (M1) and alternatively activated microglia (M2) underwent variations throughout the stages of epileptogenesis. The altered trends in the microglia-associated cytokines IL-1β, IL-4, and IL-10 paralleled the changes in phenotype proportions. We found that intraperitoneal injections of IL-4 and IFN-γ, which have been reported to modulate the phenotypes of microglia in vitro, also affected the proportion of microglia in vivo. In addition, correctly timing the modulation of the proportion of microglia improved the outcomes of epilepsy based on the reduced frequency, duration, and severity of spontaneous recurrent seizures (SRS) and increased the performances of the mice in the Morris water maze. This study is the first to report altering the proportion of microglial phenotypes in pilocarpine-induced epileptogenesis. Intraperitoneal injection of IL-4/IFN-γ could be used to modulate the proportions of the types of microglia, and epilepsy outcomes could be improved by correctly timing this modulation of phenotypes.