Research ArticleBlood Brain Barrier

CXCL12-Induced Monocyte-Endothelial Interactions Promote Lymphocyte Transmigration Across an in Vitro Blood-Brain Barrier

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Science Translational Medicine  01 Feb 2012:
Vol. 4, Issue 119, pp. 119ra14
DOI: 10.1126/scitranslmed.3003197

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Going with the Flow

White blood cells traffic ceaselessly throughout the body, using blood vessels as their conduits. They also migrate into inflamed tissues to defend the host against microbes or to repair damaged tissue. However, in many human diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, or type 1 diabetes, white blood cells invade apparently healthy uninfected tissues and cause injury. Recent research has identified the molecular regulators (chemokine receptors and their chemokine ligands; adhesion molecules) of white blood cell transmigration out of the blood vessels and into tissues. Because there are 100 or so such molecules (used selectively when specific types of white blood cells transmigrate), it is important to identify those molecules that are most directly involved in harmful inflammation. Chemokine receptors are molecules on white blood cell surfaces that receive signals to guide cells into tissue, and they change as white blood cells transmigrate across different vessel walls. In a new study, Man and colleagues have devised an in vitro model of a specialized vessel wall of the human brain termed the blood-brain barrier (BBB). They use this elegant model to study how chemokine receptors influence and are influenced by the transmigration of white blood cells across a human BBB-like endothelial cell layer.

First, the authors coaxed a special type of human endothelial cell to form a BBB-like layer in a dual perfusion chamber. Then, they allowed human white blood cells to flow across the layer at a flow rate approximating that found in brain capillaries. Some white blood cells flowed across the layer and out of the device, whereas others transmigrated across the BBB-like endothelial layer into the lower chamber of the device. The researchers wanted to establish how chemokine receptor expression by white blood cells would alter as the cells transmigrated across the BBB. They studied a chemokine receptor termed CXCR4, which is expressed on almost all white blood cells. When they added the triggering molecule for CXCR4 to their in vitro system, unexpectedly, they found that only one cell type, monocytes, showed altered CXCR4 expression. CXCR4 appeared to deliver signals to monocytes, which empowered these cells to assist other white blood cells such as T and B cells to cross the BBB. This surprising result opens up new vistas for understanding how white blood cells and vessel wall endothelial cells “talk” to each other in inflamed tissues and should spur progress for identifying the best targets for blocking harmful inflammation in the brain.

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