Sleep-Disturbance-Induced Microglial Activation Involves CRH-Mediated Galectin 3 and Autophagy Dysregulation.
Sleep-Disturbance-Induced Microglial Activation Involves CRH-Mediated Galectin 3 and Autophagy Dysregulation.
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慢性睡眠障碍（CSD），包括失眠、睡眠时间不足和睡眠质量差，是世界范围内主要的公共卫生问题，特别是在发达国家。 CSD 是与多种神经退行性疾病和神经心理疾病相关的主要健康风险因素。有人认为，CSD 可以激活小胶质细胞 (Mg)，导致神经炎症水平增加，最终导致神经元功能障碍。然而，CSD 介导的小胶质细胞激活的详细机制仍未被探索。在这项研究中，我们使用了三周睡眠碎片化 (SF) 的小鼠来探索负责镁激活的潜在途径。我们的结果显示，SF 激活海马体 (HP) 中的 Mg，但不激活纹状体和前额皮质 (PFc) 中的 Mg。 SF 增加 HP 中促肾上腺皮质激素释放激素 (CRH) 的水平。体外机制研究表明，CRH 激活 Mg 涉及半乳糖凝集素 3 (Gal3) 上调和自噬失调。 CRH 可能会破坏溶酶体膜的完整性，导致溶酶体组织蛋白酶渗漏。 CRHR2 阻断可减轻 CRH 介导的体外对小胶质细胞的影响。与对照组相比，SF 小鼠 HP 中 Gal3 水平升高且自噬失调。综上所述，我们的结果表明 SF 介导的海马 Mg 激活涉及 CRH 介导的半乳糖凝集素 3 和自噬失调。这些发现表明，针对海马 CRH 系统可能是一种改善 CSD 介导的神经炎症和神经退行性疾病的新治疗方法。
Chronic sleep disturbances (CSDs) including insomnia, insufficient sleep time, and poor sleep quality are major public health concerns around the world, especially in developed countries. CSDs are major health risk factors linked to multiple neurodegenerative and neuropsychological diseases. It has been suggested that CSDs could activate microglia (Mg) leading to increased neuroinflammation levels, which ultimately lead to neuronal dysfunction. However, the detailed mechanisms underlying CSD-mediated microglial activation remain mostly unexplored. In this study, we used mice with three-weeks of sleep fragmentation (SF) to explore the underlying pathways responsible for Mg activation. Our results revealed that SF activates Mg in the hippocampus (HP) but not in the striatum and prefrontal cortex (PFc). SF increased the levels of corticotropin-releasing hormone (CRH) in the HP. In vitro mechanism studies revealed that CRH activation of Mg involves galectin 3 (Gal3) upregulation and autophagy dysregulation. CRH could disrupt lysosome membrane integrity resulting in lysosomal cathepsins leakage. CRHR2 blockage mitigated CRH-mediated effects on microglia in vitro. SF mice also show increased Gal3 levels and autophagy dysregulation in the HP compared to controls. Taken together, our results show that SF-mediated hippocampal Mg activation involves CRH mediated galectin 3 and autophagy dysregulation. These findings suggest that targeting the hippocampal CRH system might be a novel therapeutic approach to ameliorate CSD-mediated neuroinflammation and neurodegenerative diseases.
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影响因子：
9
作者：
Garcia-Revilla, Juan;Boza-Serrano, Antonio;Espinosa-Oliva, Ana M.;Sarmiento Soto, Manuel;Deierborg, Tomas;Ruiz, Rocio;de Pablos, Rocio M.;Angel Burguillos, Miguel;Venero, Jose L.
通讯作者：
Venero, Jose L.
影响因子：
4.6
作者：
Giannogonas P;Apostolou A;Manousopoulou A;Theocharis S;Macari SA;Psarras S;Garbis SD;Pothoulakis C;Karalis KP
通讯作者：
Karalis KP
影响因子：
13.3
作者：
Aits, Sonja;Kricker, Jennifer;Jaattela, Marja
通讯作者：
Jaattela, Marja
影响因子：
12.7
作者：
Boza-Serrano, Antonio;Ruiz, Rocio;Deierborg, Tomas
通讯作者：
Deierborg, Tomas
睡眠的转化神经科学：上下文框架。
DOI：
10.1126/science.abj8188
发表时间：
2021-10-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Grandner MA;Fernandez FX
通讯作者：
Fernandez FX