Inflammatory cell migration into the central nervous system: a few new twists on an old tale

Abstract

Understanding the mechanisms of leukocyte trafficking into the brain might provide insights into how to modulate pathologic immune responses or enhance host protective mechanisms in neuroinflammatory diseases such as multiple sclerosis. This review summarized our knowledge about the sites for leukocyte entry into the central nervous system, highlighting the routes from blood into the perivascular space and brain parenchyma through the blood-brain barrier. We further discussed the multistep paradigm of leukocyte-endothelial interactions at the blood-brain barrier, focusing on the adhesion molecules and chemokines involved in leukocyte transmigration. Luminal chemokines, which are immobilized on endothelial surfaces, initiate leukocyte integrin clustering and conformational change, leading to leukocyte arrest. Some leukocytes undergo post-arrest locomotion across the endothelial surface until interendothelial junctions are identified. Leukocytes then extend protrusions through the interendothelial junctions, in search of abluminal chemokines, which will serve as guidance cues for transmigration. Extravasating cells first accumulate in the perivascular space between the endothelial basement membrane and the basement membrane of the glia limitans. Matrix metalloproteases may be involved in leukocyte transverse across glia limitans into the brain parenchyma. The adhesion molecules and chemokine receptors provide attractive targets for neuroinflammatory diseases because of their important role in mediating central nervous system inflammation.

Figure 1

Multistep paradigm of leukocyte–endothelial interactions at the blood–brain barrier, and anatomical boundaries between blood and brain parenchyma. Individual steps leading to leukocyte extravasation and entry into the parenchyma are shown in cartoon form. The key to depiction molecular entities that mediate leukocyte–endothelial interactions is located at bottom left. Leukocytes loosely tether to endothelial cells through binding of selectins to their ligands, which are generated by carbohydrate adducts to transmembrane glycoproteins; this tethering is permissive for continued movement (rolling) as the cell is pushed forward by the shear forces of flowing blood (arrow). Selectins can be expressed by either leukocytes or endothelial cells, although only endothelial selectins are shown here. Rolling leukocytes sample the endothelial surface for luminal chemokines, which are immobilized on endothelial surfaces. Engagement of leukocyte chemokine receptors by luminal chemokines initiates signals leading to clustering and conformational change of leukocyte integrins, leading to high affinity/avidity for their ligands. High‐affinity/avidity integrins bind to their ligands (either cell‐adhesion molecules or alternative receptors) on the endothelium, and mediate leukocyte arrest and adhesion. After arrest, many leukocytes locomote across the endothelial surface until interendothelial junctions are identified. Leukocytes then extend protrusions through the interendothelial junction, in search of abluminal chemokines, which will serve as guidance cues for extravasation. Transmigration occurs in response to these abluminal chemokines, and may follow chemotactic gradients. Extravasating cells are then localized in the perivascular space, between the endothelial basement membrane and the basement membrane of the glia limitans. Entry into the brain parenchyma proper entails traversing the glia limitans and its associated basement membrane, and requires action of matrix metalloproteases.