Journal
CELL DEATH & DISEASE
Volume 13, Issue 12, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-022-05454-9
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Funding
- Fund of Nanjing Health and Family Planning Commission
- National Natural Science Foundation of China [YKK188107]
- [81803513]
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In this study, it was found that exosomes derived from oxygen-glucose-deprivation/reoxygenation-stimulated astrocytes (OGD/R-ADEXs) reduced neuronal death and promoted autophagy by targeting AMPK/mTOR signaling. The enzyme Nampt released by OGD/R-ADEXs played a vital role in regulating autophagy and ameliorating acute ischemic stroke.
Acute ischemic stroke (AIS) is a global cerebrovascular disease with high disability and mortality, which has no effective therapy. Studies have demonstrated that astrocyte-derived exosomes (ADEXs) provided neuroprotection in experimental stroke models. Nevertheless, the role of exosomes derived from oxygen-glucose-deprivation/reoxygenation-stimulated astrocytes (OGD/R-stimulated astrocytes; OGD/R-ADEXs) in AIS remains largely unknown. Here, we found that OGD/R-ADEXs significantly reduced OGD/R-induced neuronal death and promoted neuronal autophagy. These effects were reversed when astrocytes were pretreated with GW4869, an exosome secretion inhibitor, or when hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) was knocked down. Neuroprotection was also observed during treatment with OGD/R-ADEXs in vivo. Further studies showed that Nampt, played a vital effect in the regulation of autophagy, was significantly increased in OGD/R-ADEXs. Knockdown of Nampt in astrocytes abolished the above-mentioned effects of OGD/R-ADEXs. Mechanistically, Nampt increased autophagy and decreased cell death by modulating AMPK/mTOR signaling, which recognized as a key signaling pathway of autophagy after AIS. Collectively, these results showed that Nampt released by OGD/R-ADEXs ameliorated acute ischemic stroke during neuronal injury by targeting AMPK/mTOR signaling to induce autophagy. Our study revealed a new key factor in the secretion of exosomes by OGD/R astrocytes, which regulated autophagy and induced neuroprotection in a mouse stroke model.
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