Microglial Annexin A2 Deficiency Supresses Inflammatory Response to Alleviate Ischemia Reperfusion-Induced Cerebral Injury

Abstract

Abstract Cerebral stroke is one of the leading causes of mortality and disability worldwide. Cerebral ischemia followed by reperfusion (I/R) triggers inflammatory responses, apoptosis, neuronal damage, and even death, while the molecular and cellular mechanisms of neuronal injury caused by cerebral I/R are not fully understood. Here, we integrated proteome, phosphoproteome and transcriptome profile analyses in mouse hippocampiafter I/Rand revealed that the differentially expressed genes (DEGs) and proteins (DEPs) mainly fall into several immune response-related events. Among 11 common DEGs/DEPs, we identified Annexin A2 (Anxa2) was exclusively up-regulated and translocated to membrane in microglial cells in response to oxygen-glucose deprivation followed by reoxygenation (OGD/R). Microglial Anxa2 knockdown suppressed M1- and promoted M2-microglia polarization induced by OGD/R, facilitated nuclear translocation of NF-κB p65 subunit, activated NF-κB transcriptional activity in response to OGD/R, suppressed the expression of OGD/R-induced pro-inflammatory factors including TNF-a, IL-1β, and IL-6, and reduced cell apoptosis in microglial BV2 cells. The conditional medium derived from Anxa2 knockdown-BV2 cell cultures with OGD/R treatment alleviated OGD/R induced-neuronal death . Our findings revealed that microglia Anxa2 plays a critical role in ischemia cerebral injury through inflammatory responses in a cell non-autonomous manner, which might be a potential target for the neuroprotection against I/R cerebral injury.