Abstract
Ischemic stroke is a common disease of the central nervous system, and ischemic brain injury (IBI) is its main manifestation. Recently, extracellular vesicles (EVs) have been strongly related to the diagnosis and treatment of IBI. However, the underlying mechanism of their effects remains enigmatic. In the present study, we aimed to study how miR-155-5p plays a role in choroid plexus epithelial (CPE) cell-derived EVs in IBI pathology. We found that miR-155-5p expression was enriched in CPE cell-derived EVs, which were subsequently internalized by neurons, enabling the delivery of miR-155-5p into neurons. An inducible oxygen and glucose deprivation and reoxygenation (OGD/R) cell model was developed to mimic ischemic neuronal injury in vitro. miR-155-5p overexpression led to reduced neuron viability, promoted apoptosis, elevated autophagic proteins' expression, and activated NLR family pyrin domain-containing 3- (NLRP3-) related inflammasomes, thereby aggravating OGD-induced neuronal injury. A dual-luciferase reporter assay exhibited that miR-155-5p could inhibit the Ras homolog enriched in brain (Rheb) expression, a mechanism critical for miR-155-5p-mediated neuronal injury. Furthermore, a mouse IBI model was developed using the transient middle cerebral artery occlusion (tMCAO) method. Animal experiments verified that miR-155p delivery via CPE cell-derived EVs aggravated IBI by suppressing Rheb expression. In conclusion, miR-155-5p in CPE-derived EVs can aggravate IBI pathology by suppressing Rheb expression and promoting NLRP3-mediated inflammasomes, suggesting its role as a potential therapeutic target in IBI.
Highlights
Stroke is primarily classified into hemorrhagic and ischemic subtypes
Through the bioinformatics analysis of miRNA expression datasets in combination with luciferase reporter assay for miR-155 expression, we found that both miR-155-5p and GTP-binding Ras homolog enriched in brain (Rheb) protein were enriched following the Ischemic brain injury (IBI)
The choroid plexus epithelial (CPE) cells were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/R) environment, and extracellular vesicles (EVs) were subsequently isolated from the normal and OGD/R culture
Summary
Stroke is primarily classified into hemorrhagic and ischemic subtypes. less fatal, ischemia accounts for 60-80% of all types of stroke globally, significantly impacting human health and quality of life [1]. Sudden depletion of oxygen and glucose most likely induces neuroinflammation and cell death as well as secondary injury to the brain during cerebral ischemia/reperfusion (I/R) and hypoperfusion [3]. A growing body of evidence has revealed the involvement of multimodal pathophysiologies in the cerebral I/R process, resulting in diverse outcomes, such as energy depletion, oxidative stress, excitotoxicity, ion imbalance, and altered gene expression pattern-mediated brain damage and motor/cognitive dysfunctions [4]. Ischemic brain injury (IBI) is unique in that once ischemia begins, irreparable brain damage can occur within minutes to hours [5]. Accumulating evidence has pointed out Oxidative Medicine and Cellular Longevity that extracellular vesicles (EVs) possess the potential to treat I/R-induced brain injury in premature infants [9]
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