Castedo Noelia, Alfonso Amparo, Alvariño Rebeca, Vieytes Mercedes R, Botana Luis M
Departamento de Farmacología, Facultad de Veterinaria, IDIS, Universidad de Santiago de Compostela, Lugo, 27002, España.
Departamento de Fisiología, Facultad de Veterinaria, IDIS, Universidad de Santiago de Compostela, Lugo, 27002, España.
Mol Neurobiol. 2025 Apr 8. doi: 10.1007/s12035-025-04921-6.
Cyclophilins (Cyps) and CD147 receptor play a crucial role in the inflammatory responses. Chronic inflammation causes tissue damage and is a common condition of several inflammation-based pathologies as diabetes or Alzheimer´s disease. Under high glucose (HG) conditions, microglia is activated and releases inflammatory mediators. In this process the role of Cyps is unknown, so this study was aimed to investigate the profile of Cyps in microglia and their release through extracellular vesicles (EVs) under hyperglycemia. An increase in reactive oxygen species (ROS) and nitric oxide (NO) levels was observed when BV2 glia cells were incubated with HG concentration. These effects were mitigated by the Cyps inhibitor cyclosporine A (CsA), suggesting the implication of Cyps in BV2 activation. In these conditions the intracellular expression of CypA, B, C and D, as well as the membrane expression of CD147 receptor was increased. In addition, only CypA and CypC were detected in the extracellular medium. Then, the presence of Cyps inside EVs was explored as an alternative secretion route. Interestingly, under HG treatment, an increase in the levels of the four Cyps in EVs was observed. When neurons were treated with EVs derived from HG-treated glia cells, their viability was reduced and EVs were detected in cytosol neurons pointing to an EVs-Cyps neurotoxic effect. These findings provide novel insights into the relationship between Cyps and EVs in neuroinflammation in hyperglycemia conditions. The current results strengthen the role of Cyps in cell communication and its potential role in brain function under pathological conditions.
亲环蛋白（Cyps）和CD147受体在炎症反应中起关键作用。慢性炎症会导致组织损伤，是糖尿病或阿尔茨海默病等几种基于炎症的病理状况的常见情况。在高糖（HG）条件下，小胶质细胞被激活并释放炎症介质。在此过程中，Cyps的作用尚不清楚，因此本研究旨在探讨小胶质细胞中Cyps的概况及其在高血糖条件下通过细胞外囊泡（EVs）的释放情况。当BV2神经胶质细胞与HG浓度孵育时，观察到活性氧（ROS）和一氧化氮（NO）水平升高。亲环蛋白抑制剂环孢素A（CsA）减轻了这些影响，表明亲环蛋白参与了BV2的激活。在这些条件下，CypA、B、C和D的细胞内表达以及CD147受体的膜表达增加。此外，仅在细胞外培养基中检测到CypA和CypC。然后，探索了EVs内亲环蛋白的存在作为一种替代分泌途径。有趣的是，在HG处理下，观察到EVs中四种亲环蛋白的水平增加。当用来自HG处理的神经胶质细胞的EVs处理神经元时，它们的活力降低，并且在细胞溶质神经元中检测到EVs，表明存在EVs-亲环蛋白神经毒性作用。这些发现为高血糖条件下神经炎症中亲环蛋白与EVs之间的关系提供了新的见解。目前的结果强化了亲环蛋白在细胞通讯中的作用及其在病理条件下对脑功能的潜在作用。
