Microglia, generally considered to be immune cells of the central nervous system (CNS), are involved in many types of inflammatory processes in the brain. They are critical in developmental processes and are imperative for the maintenance of neuronal homeostasis. Recent studies have demonstrated that under specific polarization conditions microglia develop into different phenotypes, termed M1 and M2. However, the characterization of M1- and M2-polarized microglia and the mechanisms for regulating polarization are largely unknown. Here, we examined the characterization of LPS-treated M1 and IL-4-treated M2 microglia in vitro. The addition of M2 microglial conditioned media (CM) resulted in elongated neurite length compared with M1 microglial CM due to promotion of expression of neurotrophic factors and inhibition of toxic factors from M2 microglia. M2 microglia exhibited greater phagocytic capacity than M1 microglia. Morphology of M1 microglia were characterized by larger soma and that of M2 microglia were characterized by long processes. These characterization were converted in response to polarization switches. These results suggest that endogenous molecule in microglia control a dramatic phenotypic change but not originally different population. We found that interferon regulatory factor (IRF) 7 and IRF9 were elevated during M2-to-M1 microglia in vitro and in vivo. Thus, our findings reveal that endogenous IRF signaling including IRF7 and IRF9 implicated in switching the microglial polarization.