COMMUNICATION - CHEMOKINE RECEPTOR CCR3 FUNCTION IS HIGHLY DEPENDENT ON LOCAL PH AND IONIC-STRENGTH

The CC chemokine receptor 3 (CCR3) plays an important role in the regu lation of the migration of eosinophils, a leukocyte population involve d in many inflammatory pathologies including asthma. CCR3 binds to the CC chemokine eotaxin, a promigratory cytokine originally isolated as the key component in a model of eosinophil-induced airway inflammation . We show here that eotaxin/CCR3 binding interactions exhibit a marked sensitivity to relatively small changes in the extracellular environm ent. In particular, modest variations in the pH and the level of sodiu m chloride over a range of physiologic and near physiologic conditions had dramatic effects on eotaxin binding and CCR3-mediated cytoplasmic Ca2+ mobilization. These biochemical indices were reflected at the fu nctional level as well; small changes in pH and salt also resulted in striking changes in the migration of primary human eosinophils in vitr o. These results reveal that relatively small perturbations in extrace llular buffer conditions can yield widely disparate interpretations of CCR3 ligand binding and affinities and suggest that modulation of the tissue microenvironment might be utilized to control the affinity and efficacy of chemokine-mediated cell migration.