Although cerebral endothelial cells exhibit low endocytosis activity, selective and tightly controlled trans-cellular transport mechanisms exist, via either nonspecific endocytosis or receptor-mediated endocytosis. Nonspecific endocytosis includes fluid-phase endocytosis (the capture of soluble molecules by endothelial membrane vesicles) and adsorptive endocytosis (binding of molecules by endothelial membrane proteins) ( Gloor et al., 2001). Receptor-mediated endocytosis involves endothelial transmembrane receptors, such as the transferrin receptor ( Zheng and Monnot, 2012), the insulin receptor ( Banks et al.,

2012), and the low-density lipoprotein (LDL) receptor-related proteins (LRPs), namely LRP-1 ( Deane et al., 2008). The family of ATP-binding cassette (ABC) transporters also plays a central role as efflux transporters for a wide range of lipophilic and amphipathic natural products, Ibrutinib in vivo among which are bacterial, herbal, and fungal toxins. They act as a detoxification system by protecting neurons selleckchem from toxic compounds present in their microenvironment ( ElAli and Hermann, 2011). The drug transporters ABCB1 and ABCG2 have been shown to be highly expressed at the luminal side of endothelial cells, acting as gatekeepers by impeding toxic compounds from CNS entry and accumulation ( Figure 1B). For decades, the immune privilege of the CNS was understood as

an absence of an immune system inside the CNS, and the BBB was considered only as a barrier isolating the CNS from the peripheral immune system, preventing the entry of infectious agents and immune cells into the CNS (Pachter et al., 2003). Extensive work in the last decade unravelled the presence of a specialized intrinsic innate immune system in the CNS (Rivest, 2009), which was accompanied by several observations showing that the BBB is not a neutral and passive barrier, from an immunological point of view, Thymidine kinase but rather contributes actively to the immune response of the CNS (Muldoon et al., 2013). More precisely, several data sets

showed that the peripheral immune cells can still cross an intact BBB (Carson et al., 2006), and the latter can modulate the function and control the fate of infiltrating cells (Ifergan et al., 2008), outlining a more active role of the BBB in the CNS intrinsic innate immunity. While there is limited infiltration of peripheral immune cells into the CNS in physiological conditions, neutrophils, eosinophils, T lymphocytes, monocytes, and others can be found in the CNS parenchyma after injuries to the CNS, including infections and chronic diseases such as multiple sclerosis (MS) (Wilson et al., 2010). However, the luminal side of the BBB is in constant contact with leukocytes patrolling the barrier. The advent of in vivo imaging techniques such as two-photon microscopy has allowed for the live imaging of cells constantly patrolling the brain vasculature (Coisne et al.