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标题:Mild Endoplasmic Reticulum Stress Protects Against Lipopolysaccharide-Induced Astrocytic Activation and Blood-Brain Barrier Hyperpermeability.
时间:2020-03-26 12:33:16
DOI:10.3389/fncel.2018.00222
PMID:30104960
作者:Wang Yiwei; Chen Yinan; Zhou Qin
关键词:endoplasmic reticulum stress;astrocytes;hormesis;blood-brain barrier;neuroinflammation;neurodegeneration
出版源: 《Frontiers in Cellular Neuroscience》 ,12 :222-
摘要:Recent research has revealed that uncontrolled chronic neuroinflammation is closely associated with diverse neurodegenerative diseases, by impairing blood-brain barrier (BBB) function and astrocytic reaction. Endoplasmic reticulum (ER) stress is conventionally linked to the loss of neuronal structure and function and should be widely attenuated. This notion has been questioned by recent experimental studies, which have shown that non-harmful levels of ER stress had numerous beneficial roles against neurodegeneration, including neuroprotection and inhibition of cytokine production. Here, we investigated the mild ER stress-based regulation of LPS-induced inflammatory responses in astrocytes. Primary astrocytes were exposed to tunicamycin (TM), a compound that activates ER stress, with or without the ER-stress inhibitor sodium 4-phenylbutyrate (4-PBA) before LPS treatment. Astrocytic activation, proinflammatory factor production, and the extent of ER stress were assessed. In addition, the effect of mild ER stress on astrocytes and BBB function was determinedin vivo. Male Sprague-Dawley rats received intracerebroventricular injections of TM with or without intraperitoneal 4-PBA before LPS administration. The levels of astrocytic activation and BBB permeability were measured after treatment. Our results showed that lower doses of TM resulted in a mild ER-stress response without inducing cytotoxicity and tissue toxicity. Non-toxic ER-stress preconditioning ameliorated LPS-induced overactivation and inflammatory responses in astrocytes. Moreover, pre-exposure to non-lethal doses of TM improved LPS-induced BBB impairment and cognitive ability dysfunction in rats. However, 4-PBA, reversed the protective effect of TM preconditioningin vitroandin vivo. We conclude that mild ER stress (“preconditioning”) can alleviate LPS-induced astrocytic activation and BBB disruption. Our findings provide a better understanding for the regulatory role of ER stress in neuroinflammation and indicate that mild ER stress might have therapeutic value for the treatment of neurodegenerative diseases.
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目录:
  • Mild Endoplasmic Reticulum Stress Protects Against Lipopolysaccharide-Induced Astrocytic Activation and Blood-Brain Barrier Hyperpermeability
    • Introduction
    • Materials and Methods
      • Animals
      • Intracerebroventricular Cannula Implantation
      • Behavioral Tests
      • Drug Administration
      • Experimental Protocol and Pharmacological Treatments
        • Experiment 1 (In Vivo)
        • Experiment 2 (In Vivo)
        • Experiment 1 (In Vitro)
        • Experiment 2 (In Vitro)
      • Primary Astrocyte Cultures
      • Cell Counting Kit-8 (CCK-8) Assay
      • Enzyme-Linked Immunosorbent Assay (ELISA)
      • Western Blot Analysis
      • Immunohisto/Cytochemistry
      • Evan's Blue (EB) Extravasation
      • Statistical Analysis
    • Results
      • Low Concentrations of TM Generated Non-toxic, Mild ER Stress in Astrocytes
      • Mild ER Stress Attenuated LPS-Induced Astrocytic Inflammatory Responses and Overactivation
        • TM Inhibited IL-1β and IL-6 Production in Primary Cultured Astrocytes
        • TM Reversed LPS-Induced Astrocyte Activation
        • 4-PBA Reversed TM-Induced Suppression of Astrocytic IL-1β, IL-6, and GFAP Production
      • Mild ER Stress Ameliorated LPS-Induced Cognitive Decline
      • Mild ER Stress Attenuated LPS-Induced Astrocytic Activation in the Hippocampus
      • Mild ER Stress Alleviated LPS-Induced BBB Hyperpermeability
        • Mild ER Stress Counteracted LPS-Induced Albumin Leakage in the Hippocampus
        • Mild ER Stress Inhibited the Decreases in Hippocampal Occludin and Claudin-5 Induced by LPS
        • Mild ER Stress Reversed the Increases in Hippocampal Matrix Metalloproteinase (MMP)-2 and MMP-9 Induced by LPS
        • Mild ER Stress Reduced EB Extravasation in the LPS-Treated Rats
    • Discussion
    • Author Contributions
    • Funding
    • Acknowledgments
    • Supplementary Material
    • References

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