Regulation of Leukocyte-Endothelial Interactions

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In vertebrate animals, white blood cells play an important role in the immune system by providing protection against bacterial, fungal, and viral infections. White blood cells patrol throughout the body looking for signs of infection. This immune cell surveillance involves interactions between white blood cells and the cells lining blood vessels. White cells are recruited to areas of injury by different signals, especially molecules called chemokines. Among the family of chemokines, one member, fractalkine, is found on the surface of cells lining blood vessels, and both attracts white cells and physically attaches them to blood vessels. When fractalkine on the surface of blood vessels sticks to its binding partner, CX3CR1, present on the surface of white blood cells, this sets in motion a cascade of molecular events within white cells that cause them to become "sticky", to cross the vessel lining and to enter into the underlying tissue. However, nothing is known about how fractalkine binding to CX3CR1 affects the blood vessels themselves. Our work suggests that contact between white cells and blood vessel fractalkine not only affects the white cells, but drastically alters the shape and function of blood vessel cells themselves. We observed that such contact causes gaps to form between cells of the vessel lining, allowing further tissue infiltration of white cells. This is the first demonstration that fractalkine is not merely a passive bystander that anchors white cells, but rather, plays a fundamental role in maintaining the blood vessel barrier. The proposed research will use state-of-the-art microscopy, cell biology, and biochemical techniques to examine how engaging fractalkine on the surface of blood vessels alters the structure, function, and barrier integrity of blood vessels. By understanding the molecular details, our studies will shed light on a fundamental process of immune cell patrolling conserved among vertebrate animals.