Fig. 3

Dynamic tight junction remodelling in disease. Breakdown of the blood–brain barrier (BBB) and loss and mis-localisation of tight junction proteins leads to immune cell entry to the central nervous system (CNS). In multiple sclerosis, this results in neuroinflammation, neurodegeneration and disease progression and transendothelial migration (TEM) of peripheral blood leukocytes. Claudin-5 positive extracellular vesicles (EV) can bind to blood leukocytes to potentially facilitate TEM of leukocytes into the CNS. BBB breakdown also leads to the perivascular accumulation of plasma-derived proteins such as fibrinogen, albumin and immunoglobulin G (IgG) that is found in humans with temporal lobe epilepsy as well as in rodents injected with the seizure-inducing agent kainic acid. In rodents, glutamate released from neurons and astrocytes can bind to N-Methyl-d-aspartate receptors (NMDAR) on the brain endothelium and regulate tight junction proteins claudin-5 and occludin via upregulation of matrix metalloproteinases (MMP). Extravasation of red blood cells (RBC) following traumatic brain injury releases toxic haemoglobin and free iron culminating in generation of reactive oxygen species (ROS). Extravasation of fibrinogen and albumin activates microglia leading to secretion of MMP and basement membrane (BM) degeneration. Dashed boxes display the signalling pathways and molecules that regulate expression of claudin-5 and subsequent disassembly of the tight junction protein complexes that facilitates paracellular BBB permeability of blood-derived molecules