Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Abstract

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

Blood-brain barrier permeability following conventional photon radiotherapy – A systematic review and meta-analysis of clinical and preclinical studies

“…Conventional photon RT is a therapeutic cornerstone in brain cancer and it is commonly postulated that this treatment modality alters BBB permeability [16] , a key protective component to maintain brain tissue homeostasis. The downside of a dysfunctional BBB is that the brain tissue is more exposed to blood-borne proteins, waste products and pathogens, potentially resulting in a variation of neurological disorders such as neuroinflammatory reactions and neurodegenerative diseases [99] , [100] , [101] . On the other hand, in the context of neurological diseases and brain cancer, an increased BBB permeability can have therapeutic advantages, whereby drugs that normally have limited access to the brain parenchyma are able to better reach the diseased brain [4] .…”

Regressive Autism Spectrum Disorder: High Levels of Total Secreted Amyloid Precursor Protein and Secreted Amyloid Precursor Protein-α in Plasma

“…On the other hand, we consider that sAPPα proteins may leak from the BBB. Studies have shown that excess sAPPα can activate microglia and astrocytes ( 30 , 57 ), which contribute to BBB dysfunction ( 66 ), but it is unclear whether the sAPPα protein will leak from the damaged BBB, which needs to be further verified in animal experiments and will be a very valuable direction for our subsequent research. In conclusion, with the limitations of the current sample, we were able to obtain only peripheral blood in the hope of finding early predictive markers; in our next step, we will verify these markers in animal experiments to explore the source of all sAPP proteins.…”

Regulatory Role of Mesenchymal Stem Cells on Secondary Inflammation in Spinal Cord Injury

“… 39 When the BSCB is damaged, these inflammatory mediators can drive peripheral immune cells to the lesion site; they then polarize towards pro-inflammatory phenotypes and exhibit cytokine expression patterns similar to the resident inflammatory cells, resulting in a more severe local inflammatory response that consequently hinders neurological function recovery ( Figure 1 ). 40 , 41 A sequential inflammatory cascade is switched on following SCI. Neutrophils are driven to the lesion site within 24 hours and facilitate phagocytosis and the removal of cellular debris; many neutrophils also secrete distinct oxidative and tissue-degrading enzymes, proteases, reactive oxygen species (ROS), and tumor necrosis factor (TNF)-α, creating a harmful microenvironment that is neurotoxicity to neurons.…”