Effects of matrix metalloproteinase processing of chemokines on inflammation

Inflammation is the response of the body to infection or injury, triggered by the release of proteins that initiate inflammation. Amongst these proteins are members of the chemokine family. Chemokines act as biological beacons, guiding the migration of white blood cells (WBC) from blood vessels to the affected tissue. The structure of chemokines is important to their function. One end of the chemokine binds to tissue and vessels to create a path for white blood cells to follow; the other end interacts with a receptor on the surface of the WBC, prompting the release of further inflammatory mediators that spread the inflammatory response. Recruited and activated WBC attempt to isolate and destroy infectious agents and to prevent further damage. WBC – and in particular cells called macrophages – then help resolve the inflammatory response. In chronic inflammation, continual recruitment and activation of macrophages results in excessive production of reactive molecules that cause host tissue damage, as observed in diseases such as rheumatoid arthritis, multiple sclerosis and chronic obstructive pulmonary disease. The apparent deregulation of macrophage movement may be a result of a change in the structure and function of chemokines. Matrix metalloproteinases (MMPs) are a family of enzymes that modulate chemokine activity by cutting off a portion of either end of the chemokine, which keeps it from functioning properly. Amanda Starr is looking at the functional effects of MMP cleavage on chemokines that recruit and activate macrophages, determining whether cut chemokines are more able to attract and activate macrophage-like cells. She is also developing a technique for detection and quantification of both full-length and cut forms of chemokines from tissue samples. Ultimately, this knowledge could lead to more appropriate and directed therapeutics for the treatment of chronic inflammatory diseases.