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Updated: May 12, 2025
Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
The foam cell-derived exosomes exacerbate ischemic white matter injury via transmitting metabolic defects to
Hang Zhang1, Luo-Qi Zhou1, Sheng Yang1
1Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract:
Atherosclerosis (AS) has been shown to be an independent risk factor for vascular cognitive impairment (VCI), but the mechanisms remain unclear. Here, we found that AS circulating exosomes exacerbated ischemic white matter injury and VCI. Exosomes originating from macrophage-derived foam cells targeted microglia. Mechanistically, foam cell-derived exosomes transmitted redox imbalance, mitochondrial dysfunction, and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis. Anti-miR-101-3p or activation of Nrf2, both genetically and pharmacologically, could antagonize AS exosomes and ameliorate VCI. In conclusion, our findings reveal a distant connection between peripheral macrophages and brain microglia, which provides new insights and potential targets of AS-induced VCI.
Insights
Atherosclerosis (AS) circulating exosomes worsen brain white matter injury and vascular cognitive impairment (VCI). Targeting the miR-101-3p-Nrf2 axis in microglia may offer therapeutic strategies for AS-related VCI.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Cell Biology
Background:
- Atherosclerosis (AS) is a known risk factor for vascular cognitive impairment (VCI).
- The precise mechanisms linking AS to VCI, particularly the role of exosomes, are not fully understood.
- Understanding these mechanisms is crucial for developing effective treatments for VCI.
Purpose of the Study:
- To investigate the role of circulating exosomes from atherosclerotic lesions in exacerbating ischemic white matter injury and VCI.
- To elucidate the molecular mechanisms by which these exosomes affect brain cells, specifically microglia.
- To identify potential therapeutic targets for mitigating AS-induced VCI.
Main Methods:
- Utilized exosome isolation and characterization techniques.
- Administered AS-derived exosomes to induce white matter injury and VCI in a model system.
- Investigated the targeting of microglia by foam cell-derived exosomes.
- Analyzed the transmission of redox imbalance, mitochondrial dysfunction, and metabolic defects via the miR-101-3p-Nrf2-Slc2a1 axis.
- Employed anti-miR-101-3p and Nrf2 activation (genetic and pharmacological) to assess therapeutic potential.
Main Results:
- AS circulating exosomes were found to exacerbate ischemic white matter injury and VCI.
- Exosomes from macrophage-derived foam cells specifically targeted microglia.
- These exosomes transmitted cellular damage pathways (redox imbalance, mitochondrial dysfunction, metabolic defects) to microglia through the miR-101-3p-Nrf2-Slc2a1 axis.
- Inhibition of miR-101-3p or activation of Nrf2 ameliorated the effects of AS exosomes and improved VCI outcomes.
Conclusions:
- Peripheral AS macrophages communicate with central brain microglia via circulating exosomes.
- The miR-101-3p-Nrf2-Slc2a1 pathway is a key mediator of exosome-induced VCI.
- Targeting this pathway presents a promising therapeutic strategy for AS-induced VCI.
