Hypoxic Microglial Extracellular Vesicles Abrogate Poststroke AQP4 Depolarization, Astrogliosis and Neuroinflammation

by Wenqiang Xin
Doctoral thesis
Date of Examination:2023-11-02
Date of issue:2023-11-03
Advisor:Prof. Dr. Thorsten Roland Döppner
Referee:Prof. Dr. Thorsten Roland Döppner
Referee:Prof. Dr. Gerald Georg Wulf
Persistent Address: http://dx.doi.org/10.53846/goediss-10150

 

 

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Abstract

English

Reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation occurring and lasting for a long time in the periinfarct region are associated with poststroke brain injury. Our previous work has revealed that extracellular vesicles (EVs) from hypoxic microglia are implicated in protecting against stroke-induced brain damage. Uncertainty persists regarding how poststroke immunological regulation and AQP4 depolarization are affected by hypoxia- induced microglial EVs. Mice were administered with hypoxic microglial EVs via tail vein injections. Cerebral perfusion, edema of the brain, and neurological function were detected after induction of ischemia in the MCAO mouse model. AQP4 polarization, astrogliosis, and neuroinflammation were evaluated in the brain cortex after ischemia. Employing primary astrocytes and microglia subjected to oxygen-glucose deprivation (OGD) in vitro, we evaluated the role of EVs in microglial polarization and astrocytic inflammation and AQP4 expression. Furthermore, a notion is given to the role of AQP4 levels in astrocyte–microglia inflammation communication via establishing a co-culture system between primary astrocytes and microglia. In vivo, EVs from hypoxic microglia promote postischemic cerebral perfusion and motor coordination impairment and diminished postischemic brain edema. Such EVs in the meantime cut peri-infarct AQP4 depolarization, astrogliosis, and inflammation. In vitro, a hypoxic condition promoted cortical M2 microglial polarization, and an increased concentration of such EVs in hypoxic microglia was related to a higher release of the M2 microglial polarization biomarkers and a lower release of the M1 microglial polarization biomarkers. Furthermore, EVs attenuated the upregulation of AQP4 clustering and pro-inflammatory molecules in the cortical astrocytes challenged by hypoxia. However, an alteration of the AQP4 expression in astrocytes was not involved in modulating astrocyte- to-microglia inflammation communication. Therefore, the data illustrate, for the first time, that hypoxic microglia can participate in protecting against stroke-induced brain damage by diminishing poststroke neuroinflammation, astrogliosis and AQP4 depolarization via releasing EVs, indicating that this investigation may represent a novel perspective for stroke treatment.
Keywords: AQP4; extracellular vesicles; microglia; astrocyte; stroke
 
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