Glucocorticoids and endothelial cell barrier function

Abstract

Glucocorticoids (GCs) are steroid hormones that have inflammatory and immunosuppressive effects on a wide variety of cells. They are used as therapy for inflammatory disease and as a common agent against edema. The blood brain barrier (BBB), comprising microvascular endothelial cells, serves as a permeability screen between the blood and the brain. As such, it maintains homeostasis of the central nervous system (CNS). In many CNS disorders, BBB integrity is compromised. GC treatment has been demonstrated to improve the tightness of the BBB. The responses and effects of GCs are mediated by the ubiquitous GC receptor (GR). Ligand-bound GR recognizes and binds to the GC response element located within the promoter region of target genes. Transactivation of certain target genes leads to improved barrier properties of endothelial cells. In this review, we deal with the role of GCs in endothelial cell barrier function. First, we describe the mechanisms of GC action at the molecular level. Next, we discuss the regulation of the BBB by GCs, with emphasis on genes targeted by GCs such as occludin, claudins and VE-cadherin. Finally, we present currently available GC therapeutic strategies and their limitations.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…In support of these claims, dexamethasone is known to restore the integrity of the BBB and has limited cerebrospinal fluid penetration. 51,52 Additionally, in studies of experimental autoimmune encephalomyelitis (EAE), a well-established rodent model of multiple sclerosis (MS), dexamethasone treatment induced apoptosis and inhibited the CNS migration of peripheral, bystander T cells with limited impact on CNS-resident, antigen-specific T cells. 35,53 Taken together, these data suggest there may be variability of corticosteroid’s influence on CNS-resident vs. peripheral T cells, and the current study’s findings demonstrate that anti-PD-1-mediated immune responses against intracranial tumors may potentially go undeterred in the setting of corticosteroids.…”

Managing Disease and Therapy-Related Complications in Patients with Central Nervous System Tumors

“…Seventy to 100 % of primary and secondary brain tumor patients are treated with corticosteroids at some point in their management [6]. Although the exact mechanism of action of corticosteroids is not fully understood, it is proposed that they modulate the endothelial cells of the blood-brain barrier cells thereby decreasing permeability and extravasation of fluid [7].…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Because TJCs greatly reduce paracellular diffusion between endothelial cells, BMVECs are tasked with regulating the transcellular routes that shuttle materials across the BBB endothelium. Lipophilic molecules (such as steroid hormones) readily pass through the BMVEC plasma membrane and across the cell to access targets in the CNS [169,170]. As mentioned earlier, transporter proteins like GLUT-1 selectively transport their substrates from the luminal to abluminal plasma membrane, while other transporters like P-gp function to restrict potentially harmful molecules from crossing the basal, endothelial plasma membrane [163].…”