Overview of Research
Chemokines and their receptor are best known for their role in immune surveillance, where they control the migration and activation of leukocytes to resolve physiological abnormalities such as infection and cancer. However, inappropriate regulation of these proteins is associated with an extraordinary number of pathologies including inflammatory disease, atherosclerosis, cancer and AIDS. Thus there is significant interest in understanding how they function in order to develop drugs to block their activities. In recent years, it has become clear that chemokine-induced cell migration is a complex multistep process involving many different interactions, not only of chemokines with chemokine receptors, but also with glycosaminoglycans (GAGs) and with each other through homo- and hetero-oligomerization.
In the context of inflammation, leukocyte migration from the blood into the extravascular space involves the following general steps which are illustrated in the figure. Upon injury or infection, cells secrete chemokines (blue balls) which accumulate on endothelial cell and extracellular matrix GAGs as a mechanism for chemokine localization whereby they provide directional signals for migrating cells, especially in the presence of blood flow. When secreted from extravascular cells, chemokines must first be transcytosed across the endothelium to the luminal surface of the cells in order to encounter leukocytes in the blood, and this transport process also involves chemokine:GAG interactions. Leukocytes initially "roll" along the endothelium through labile interactions involving selectins (not shown) in order to sense their microenvironment. However, upon encountering GAG-immobilized chemokines, the engagement of chemokines with their GPCRs on the leukocytes leads to leukocyte arrest through activation of integrins into their high affinity state. Once arrested, further interactions between chemokines and receptors cause the leukocytes to extravasate through endothelial cells into the surrounding tissue along chemokine gradients. While the molecular players and the overall process of cell migration are reasonably well-described, the molecular details are not. Indeed, there are several discrete steps involving chemokines where it is unclear how different chemokine structures and interactions are integrated into the entire process. Our laboratory uses a combination of structural biochemical and cell biological approaches to understand the molecular basis of chemokine function, which clearly involves dynamically changing interactions and structures.