Gliotransmitters and cytokines in the control of blood-brain barrier permeability

Abstract

The contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

“…Activated astrocytes and microglial cells release neuroactive “gliotransmitters” via exocytosis, akin to neurotransmitter release from nerve endings ( 71 ), and alter neuronal chloride ( 72 ). They modulate blood–brain barrier permeability and BBB-mediated neuroinflammation and affect cell-to-cell communication ( 73 ). Gliotransmitters include GABA and taurine (inhibitory gliotransmitters) ( 72 ), as well as glutamate, d -serine, ATP, and l -lactate ( 71 ).…”

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

“…Recent scientific advances point toward the alterations in the inherent metabolic machinery of reactive glial cells as a result of the excessive demands of the overall brain tissue, as well as the individual cellular demands in disease state, resulting in altered neuron-glial interactions. The gliotransmitters (e.g., ATP, glutamate, and D-serine) released by glial cells impact the neuronglia communication (Osipova et al, 2018). It has been reported that impaired signaling between the microglia and neurons plays a significant role in the cognitive decline in AD, while the aberrant calcium and glutamate signaling in the reactive astrocytes also plays an important role in neuropathology (Teaktong et al, 2003;Lim et al, 2013).…”

Neuroinflammation and Neuromodulation in Neurological Diseases

“…Glutamate, an excitatory neurotransmitter essential for most brain activities, has been considered relevant to the pathogenesis of neuroinflammation, contributing to the development of several acute and chronic brain injuries [13]. The main process responsible for maintaining extracellular glutamate levels below toxic concentrations, thus favoring the physiological glutamatergic tonus, is the glutamate uptake activity of glutamate transporters located in neural cell membranes, mainly in astrocytes [14].…”