Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke

Background: elevated plasma homocysteine (hcy) levels have been indicated as a strong and modifiable risk factor of ischemic stroke; the previous studies have shown that exposure to hcy activates cultured microglia. however,whether neurotoxicity of hcy involves microglia activation following brain ischemia and the underlying mechanisms remains incompletely understood. methods: the cerebral damage was evaluated by staining with 2,3,5-triphenyltetrazolium chloride,hematoxylin-eosin,and fluoro jade b. the activation state of microglia was assessed via immunoreaction using the microglial markers iba1 and ox-42. then,the inflammatory factors such as tumor necrosis factor α (tnf-α),interleukin 6 (il-6),and phosphorylated signal transducer and activator of transcription 3 (pstat3) were examined by western blot analysis and fluorescence immunohistochemistry. results: elevated hcy level augmented brain damage and neural cell toxicity in the brain cortex and the dentate gyrus region of the hippocampus after cerebral ischemia/reperfusion. meanwhile,hcy activated microglia and induced the expression of the inflammatory factors such as tnf-α and il-6. moreover,hcy caused an increase in pstat3 expression which occurs in microglial cells. ag490,a jak2-stat3 inhibitor,effectively inhibited the phosphorylation of stat3,microglial cell activation and the secretion of il-6,tnf-α raised by hcy treatment. conclusions: stat3 signaling pathway located in microglia plays a critical role in mediating hcy-induced activation of microglia and neuroinflammation in rat mcao model. this suggests the feasibility of targeting the jak2/stat3 pathway as an effective therapeutic strategy to alleviate the progression of hcy-associated ischemia stroke. © 2017 the author(s).