Immune surveillance of the BBB is critical for the organism to respond to threats to the CNS. Leukocytes in the circulation bind endothelial cells of the BBB through adhesion molecules such as VCAM-1 and ICAM-1, sensing for distress signals from the CNS. Such a signal may be mediated via chemokines and cytokines released by microglia, astrocytes, and pericytes (Takeshita and Ransohoff, 2012). The exact
mechanisms of transmigration PF-01367338 in vivo into the CNS are still unknown, although it is believed to occur by paracellular means, implying a loosening of the TJ between endothelial cells of the BBB (Sagar et al., 2012). While detrimental in certain pathological cases such as multiple sclerosis, the recruitment of leukocytes into the CNS can play a beneficial role to help resident microglia in resolving certain insults (Simard et al., 2006) or even in gene therapy replacements (Cartier et al., 2009). The BBB, however, is not without fault. Under constant attack by pathogens, tightly regulated processes can become detrimental and actually contribute to the development of an infection. Pathogens enter into the CNS either by paracellular (between endothelial cells) or by trans-cellular (through them) mechanisms ( Ley et al., 2007; Bencurova et al., 2011). As a basic first line of defense, TJs are challenged by some infectious agents in order to weaken the physical properties
of the BBB and infiltrate the CNS. The viral glycoprotein gp120 of HIV has been shown to breach the BBB by activating GPCR Compound Library molecular weight the chemokine receptors C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4) ( Kanmogne et al., 2005; András et al., 2005), resulting in TJ protein proteolytic degradation via proteasome ( Nakamuta Liothyronine Sodium et al., 2008; Wang et al., 2011). On the other hand, the meningococcal type IV pili bacteria have been reported to
infiltrate into the CNS by recruiting the polarity complex Par3/Par6/PKCzeta that governs TJ formation at the luminal side of the BBB. This results in the formation of ectopic intercellular junctional domains at the site of bacteria-cerebral endothelial cell interaction, depleting TJ proteins and consequently breaching the BBB ( Coureuil et al., 2009). Moreover, these bacteria can take advantage of the biased β2-adrenoceptor/β-arrestin signaling pathway in endothelial cells in order to tightly adhere to the luminal side of BBB and to delocalize TJ proteins, thus creating anatomical gaps through the BBB that bacteria can use to infiltrate into the CNS ( Coureuil et al., 2010). Transport mechanisms can also be used to trick cerebral endothelial cells into letting infectious agents cross the BBB. The adsorptive endocytosis takes place when glycoproteins in cerebral endothelial cell membrane bind other glycoprotein ligands in a lectin-like fashion.