Studying stress in BV2 microglial cells: from model development to translational perspectives

Chronic stress is a major risk factor for neuropsychiatric disorders. At the brain level, stressors elicit activation of the HPA axis and consequent glucocorticoid (GC) release. While acute GC signaling promotes adaptive responses through balance between mineralocorticoid (MR) and glucocorticoid (GR) receptors, chronic exposure leads to a dysregulated GR-driven state, consistently implicated in such conditions. Microglia, highly responsive to stress-related cues, act as mediators of the stress-induced neurobiological changes underlying neuropsychiatric disorders. To model the impact of chronic exposure to stress on microglial function in vitro, the BV2 murine microglial cell line was treated for 96h with increasing concentrations of corticosterone (CORT), the principal GC in rodents, to mimic prolonged signalling. CORT treatment induced a GC profile consistent with chronic stress, as it exhibited an ‘MR-GR switch’ imbalance shifted towards GR. This was coupled with an impairment of its FKBP5-mediated negative feedback mechanism. In line with existing literature, these data support the model’s validity and broader applicability for investigating stress-driven alterations across cellular pathways. First, the inflammatory response was evaluated given microglia’s role in neuroinflammation, key feature of neuropsychiatric conditions: CORT triggered a pro-inflammatory reaction characterised by increased interleukin-6 levels. While previous results showed a dose-dependent response across all tested concentrations, CORT induced a non-linear modulation of anti-inflammatory arginase-1, with upregulated expression at intermediate concentrations followed by a return to baseline, suggesting an adaptive response at lower stress levels, whereas the capacity to counteract the challenge might no longer be sustained beyond a certain threshold. A similar pattern was found for antioxidant catalase activity, which displayed a significant decrease only at higher concentrations. Hence, this model may offer valuable insights into stress-related molecular changes and serve as a platform to evaluate potential therapies. Furthermore, it could complement existing in/ex vivo models to improve our understanding of such alterations in humans.