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Aims This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes. Methods In vivo, middle cerebral artery occlusion ( MCAO) was induced in both FasL-mutant ( gld) and wild-type (wt) mice. In vitro, primary cortical neuron or microglia or coculture from wt/ gld mice was subjected to oxygen glucose deprivation ( OGD). sFasL level in the supernatant was evaluated by ELISA. Neuronal-conditioned medium (NCM) or exogenous sFasL was applied to primary microglia with or without FasL neutralizing antibody. Protein expression of JAK2/ STAT3 and NF-κB pathways were determined by Western blot. The effect of microglia phenotype from wt/ gld mice on the fate of ischemic neurons was further elucidated. Results In vivo, compared with wild-type mice, M1 markers ( CD16, CD32 and iNOS) were attenuated in gld mice after MCAO. In vitro, post- OGD neuron released more sFasL. Both post- OGD NCM and exogenous sFasL could trigger M1-microglial polarization. However, this M1 phenotype shift was partially blocked by utilization of FasL neutralizing antibody or gld NCM. Consistently, JAK2/ STAT3 and NF-κB signal pathways were both activated in microglia after exogenous sFasL treatment. Compared with wild-type mice, M1-conditioned medium prepared from gld mice protected neuron against OGD injury. Conclusions Ischemic neurons release sFasL, which contributes to M1-microglial polarization. The underlying mechanisms may involve the activation of JAK2/ STAT3 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]