The glucocorticoid receptor regulates epileptic activity and neuroinflammation via blood-brain barrier endothelial signaling in a mouse model of epilepsy

The blood-brain barrier (BBB) is a tightly regulated cellular compartment which separates the blood from the central nervous system (CNS). It consists of tightly adhered endothelial cells, pericytes and glia limitans which together act as a gateway and as an interface between the blood and CNS parenchyma. However, the role of the BBB in initiating, propagating and dampening brain inflammation in conditions involving infection, chronic stress or epilepsy is not fully explored. We therefore sought to elucidate the role of the glucocorticoid receptor (GR)-a key immune regulator-in brain endothelial cells during brain inflammation. To this end, we developed a conditional and endothelial-specific GR knockout (KO) mouse model, to elucidate the role of endothelial GR in epileptic seizures, which are known to induce both neuroinflammation and secretion of corticosterone due to activation of the hypothalamus-pituitary-adrenal (HPA) axis. In our epilepsy model of pentylenetetrazol (PTZ) injection, the endothelial-specific GR KO mice showed a significantly worsened seizure phenotype as compared with littermate controls. This response was accompanied by upregulation of several important immune factors such as interleukin (IL)-6 and cyclooxygenase 2 (COX-2), which are known to contribute to epileptic activity. In addition, immunohistochemistry analysis revealed a pronounced expression of glial fibrillary acidic protein (GFAP) and CD68, which indicate the activation of astrocytes and microglia, respectively. Together, our results suggest multifactorial effects of the BBB on neuroinflammation, which is regulated by the GR in BBB endothelial cells, presumably as part of feedback inhibition mediated by the HPA axis.