Fig. 4

Entry of circulating immune cells into the brain. Entry of immune cells from the periphery into the CNS occurs through a multi-step process, which is initiated by leukocyte capture by the endothelium. Communication between chemokines and chemokine receptors causes activation of leukocytic integrins and enables their interaction with endothelial ICAM-1 and VCAM-1, creating a firm adhesion. After this adhesion is established, the leukocyte crawls along the endothelium – again mediated by chemokine expression – until it enters the brain either through an endothelial cell (transcellular diapedesis) or via an inter-endothelial junction (paracellular diapedesis). After entering the brain, the leukocyte can secrete various molecules – such as cytokines, free radicals, and matrix metalloproteinases – that weaken the tight junctions, change the BBB’s transport properties or degrade the basement membrane, thus further reducing the integrity of the blood-brain barrier. Figure was originally published by Wevers & De Vries (2015) and reused for this manuscript with the copyright holder’s permission