Receptor trees in chemokine forests

Chemokines are small proteins that direct the migration of all leukocyte classes. One would think that 2 or 3 distinct chemokines would be sufficient to ensure that white blood cells properly home to sites of inflammation. But there are at least 40 chemokines and 18 receptors, with new ones still being discovered. Surprisingly, many of the chemokines bind several receptors, and receptors are often promiscuous, being activated by many different chemokines. Chemokine receptor function has been obscured by the multitude of potential inteactions that all appear to lack distinct activities. Why are so many chemokines binding to so many receptors?

Weber et al (page 1144) provide an answer: activating different receptors produces distinct functions. Although this might seem obvious, the concept has been extremely difficult to prove. Leukocytes migrate from the bloodstream to inflamed tissue in 4 distinct steps: rolling along the vessel wall, arrest, spreading, and finally migration through the endothelium. Weber et al found that during this process the chemokine RANTES activates 2 different receptors, CCR1 and CCR5. They found that CCR1 activation was responsible for arrest in shear flow, while CCR5 contributed to spreading of the cell along the vessel wall. Both receptors contributed to movement through the endothelium.

Why is this important? Chemokine receptors play extremely important roles in human disease, from HIV infection to cardiovascular disease to autoimmune disorders. Previously it was thought that to inhibit chemokine contributions to disease one would have to target a large number of receptors. The present study raises the possibility that single receptors on specific cell types can be targeted to antagonize specific steps in pathologic leukocyte migration. Further analysis of narrow functional differences of chemokine receptors will help realize their enormous therapeutic potential.