Cyclophilin A and C are the Main Components of Extracellular Vesicles in Response to Hyperglycemia in BV2 Microglial Cells

Abstract

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.

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