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A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

ABSTRACT: Ischemia and hypoxia activate astrocytes into reactive types A1 and A2, which play roles in damage and protection, respectively. However, the function and mechanism of A1 and A2 astrocyte exosomes are unknown. After astrocyte exosomes were injected into the lateral ventricle, infarct volume, damage to the blood-brain barrier (BBB), apoptosis and the expression of microglia-related proteins were measured. The dual luciferase reporter assay was used to detect the target genes of miR-628, and overexpressing A2-Exos overexpressed and knocked down miR-628 were constructed. qRT-PCR, western blotting and immunofluorescence staining were subsequently performed. A2-Exos obviously reduced the infarct volume, damage to the BBB and apoptosis and promoted M2 microglial polarization. RT-PCR showed that miR-628 was highly expressed in A2-Exos. Dual luciferase reporter assays revealed that NLRP3, S1PR3 and IRF5 are target genes of miR-628. After miR-628 was overexpressed or knocked down, the protective effects of A2-Exos increased or decreased, respectively. A2-Exos reduced pyroptosis and BBB damage and promoted M2 microglial polarization through the inhibition of NLRP3, S1PR3 and IRF5 via the delivery of miR-628. This study explored the mechanism of action of A2-Exos and provided new therapeutic targets and concepts for treating cerebral ischemia.

SUBMITTER: Wang Y

PROVIDER: S-EPMC11332600 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

Wang Yingju Y Li He H Sun Hanwen H Xu Chen C Sun Hongxue H Wei Wan W Song Jihe J Jia Feihong F Zhong Di D Li Guozhong G

Journal of cellular and molecular medicine 20240801 16

Ischemia and hypoxia activate astrocytes into reactive types A1 and A2, which play roles in damage and protection, respectively. However, the function and mechanism of A1 and A2 astrocyte exosomes are unknown. After astrocyte exosomes were injected into the lateral ventricle, infarct volume, damage to the blood-brain barrier (BBB), apoptosis and the expression of microglia-related proteins were measured. The dual luciferase reporter assay was used to detect the target genes of miR-628, and overe ...[more]

PMID: 39159174

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Project description:Macrophages play a critical role in the development of acute ischemic stroke (AIS). Cerebral ischemia-reperfusion injury (CIRI) is a pivotal pathological process that exacerbates AIS, with exosomes act as crucial mediators. However, the effects and mechanisms of action of macrophage-derived exosomes on CIRI remain unclear. This study demonstrated that macrophage-derived exosomes induce endothelial ferroptosis and barrier disruption during CIRI. Through proteomic sequencing and the reanalysis of transcriptomic and single-cell sequencing data, thrombospondin-1 (THBS1) was identified as a key exosomal molecule. Elevated THBS1 was observed in exosomes and monocytes from the peripheral blood of patients with AIS in oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated THP-1 and RAW264.7, in their secreted exosomes, and in macrophages within the brains of transient middle cerebral artery occlusion (tMCAO) mice. Additionally, THBS1 expression in exosomes was positively correlated with vascular barrier injury biomarkers, including MMP-9 and S100B. Modulation of THBS1 in macrophage-derived exosomes affected exosome-induced ferroptosis in endothelial cells. The mechanism by which THBS1 binds directly to OTUD5 and promotes GPX4 ubiquitination was elucidated using RNA interference, adeno-associated virus transfection, and endothelial-specific Gpx4 knockout mice. High-throughput screening of small-molecule compounds targeting THBS1 was performed. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays further confirmed that salvianolic acid B (SAB) has a potent binding affinity for THBS1. SAB treatment inhibited the interaction between THBS1 and OTUD5, leading to reduced GPX4 ubiquitination. Further research revealed that SAB treatment enhanced the cerebral protective effects of THBS1 inhibition. In conclusion, this study explored the role of exosome-mediated signaling between macrophages and cerebral vascular endothelial cells in CIRI, highlighting the THBS1-OTUD5-GPX4 axis as a driver of endothelial ferroptosis and brain injury. Targeting this signaling axis represents a potential therapeutic strategy for treating CIRI.

Dataset Information

A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

Publications

A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

Similar Datasets

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