Blood, 15 February 2001, Vol. 97, No. 4, pp. 833-833
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.
Robert Hromas
Indiana University Medical Center
