HABP2 Encapsulated by Peripheral Blood-Derived Exosomes Suppresses Astrocyte Autophagy to Exacerbate Neuroinflammatory Injury in Mice with Ischemic Stroke

Abstract

Exosomes are shown to be involved in the regulation of neuroinflammatory injury. The current study analyzed how peripheral blood-derived exosomes affected hyaluronan-binding protein 2 (HABP2) expression to regulate neuroinflammatory injury after ischemic stroke (IS). An IS animal model was stimulated by middle cerebral artery occlusion (MCAO), followed by injection of lentivirus. Peripheral blood samples were collected from MCAO mice after different treatments. The cerebral infarction volume, astrocyte activation, and neuroinflammation were observed by TTC staining, immunofluorescence, and ELISA, respectively. HABP2 was highly expressed in the brain tissues of MCAO mice. Also, an enhancement of HABP2 was noted in their peripheral blood-derived exosomes, while loss of HABP2 in peripheral blood-derived exosomes promoted the astrocyte autophagy and reduced the release of the inflammatory factors as well as the apoptosis of neuronal cells. PAR1 overexpression reversed the effect of HABP2 loss on autophagy and neuroinflammation in MCAO mice. Additionally, the agonist of the PI3K/AKT/mTOR pathway, SC79, could also reverse the effect of sh-PAR1 on neuroinflammation. Mechanistically, HABP2 enhanced PAR1 to activate the PI3K/AKT/mTOR pathway, thereby suppressing cell autophagy. Overall, HABP2 in peripheral blood-derived exosomes can activate the PAR1/PI3K/AKT/mTOR pathway to reduce autophagy and aggravate neuroinflammatory injury after IS.

Observing Extracellular Vesicles Originating from Endothelial Cells in Vivo Demonstrates Improved Astrocyte Function Following Ischemic Stroke via Aggregation-Induced Emission Luminogens

“…Interestingly, recent studies have demonstrated the effects of proteins and nucleic acids carried by EVs on astrocyte function. For example, tumor necrosis factor-stimulated gene-6 carried by stem cell-derived EVs, tau proteins carried by neuron-derived EVs, and hyaluronan-binding protein 2 carried by peripheral blood-derived EVs could modulate the function of astrocytes under different conditions. − Additionally, nucleic acids, such as miR-146a carried by stem cell-derived EVs and miR-1290 carried by breast cancer cell-derived EVs could regulate the biological function of astrocytes. , Nevertheless, the role of HUVEC-EVs in modulating the astrocyte function remains unclear. Since HUVEC-EVs have neuroprotective effects against IS, it is possible that nucleic acids and proteins carried by HUVEC-EVs would participate in this process via targeting astrocytic function.…”

“…For example, tumor necrosis factor-stimulated gene-6 carried by stem cell-derived EVs, tau proteins carried by neuron-derived EVs, and hyaluronan-binding protein 2 carried by peripheral blood-derived EVs could modulate the function of astrocytes under different conditions. 43 − 45 Additionally, nucleic acids, such as miR-146a carried by stem cell-derived EVs and miR-1290 carried by breast cancer cell-derived EVs could regulate the biological function of astrocytes. 46 , 47 Nevertheless, the role of HUVEC-EVs in modulating the astrocyte function remains unclear.…”