Abstract Number ‐ 62: Inhibiting neuron‐immune axis in acute stroke reverses microglia‐induced neuroinflammation

Abstract

Introduction Stroke is a major cause of adult disability and death worldwide. The subsequent development of neuroinflammation 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 microglia M1 polarization and the interaction between microglia and neuron within the stroke area remain unclear. Methods Using a murine middle cerebral artery occlusion (MCAO) model and chemogenetics, we manipulated neuronal activity to study whether neuronal activity modulates microglia polarization and whether manipulating this neuron‐immune axis prevents neuroinflammation after stroke. Results Our findings demonstrate that the abnormal neuronal activation and depolarization induced by brain ischemia drive microglial proinflammatory M1 polarization through neuron‐derived exosome secretion through activating the NF‐kB pathway. Inhibiting the ischemia‐induced neuronal activity reversed this microglial M1 polarization and decreased the pro‐inflammatory cytokines in the mouse brain. In addition, midazolam administration inhibited the abnormal neuronal activity and the microglia pro‐inflammatory polarization. Conclusions Together, these findings indicate that inhibiting abnormal neuronal activation triggered by ischemia prevents the microglia‐induced neuroinflammation that could protect the brain from secondary brain damage.