Background Stroke is a major cause of adult disability and death worldwide. The subsequent development of neuroinflammation after reperfusion dramatically increases the risks associated with stroke. Microglia are key immune cells that respond to microenvironmental changes during ischemic stroke. The M1 subtype of microglia is a proinflammatory phenotype that promotes neuroinflammation-induced secondary brain damage. However, the mechanism of stroke-induced microglial M1 polarization and the interaction between microglia and neurons within the stroke area remain unclear.
Methods Using a murine middle cerebral artery occlusion (MCAO) model and chemogenetics, we studied whether neuronal activity modulates microglia polarization and whether targeting this neuron-immune axis prevents neuroinflammation after stroke.
Results Our findings demonstrate that ischemic/hypoxic stimulation sensitizes neurons to glutamate and causes abnormal neuronal activation. This neuronal excitotoxicity drives microglial proinflammatory M1 polarization through neuron-derived exosome secretion via NF-kB activation. Inhibiting the ischemia-induced neuronal activity reversed this microglial M1 polarization and decreased levels of pro-inflammatory cytokines in the mouse brain. We are currently testing whether medications that inhibit neuronal excitotoxicity and the microglia’s pro-inflammatory polarization reverse this secondary brain injury.
Conclusion Together, these findings indicate that ischemic/hypoxic-induced neuronal excitotoxicity promotes neuroinflammation in the setting of reperfusion after ischemic stroke. Inhibiting abnormal neuronal activation triggered by ischemia may prevent microglia-induced neuroinflammation that could protect the brain from secondary brain damage.
Disclosures X. Guo: None. D. Xin: None. W. Qiu: None. G. Li: None. Z. Wang: None.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.