Neuronal Soluble Fas Ligand Drives M1-Microglia Polarization after Cerebral Ischemia.

ABSTRACT: 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-?B 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-?B 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-?B signaling pathways.

SUBMITTER: Meng HL 

PROVIDER: S-EPMC6492913 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature