Abstract
The CC chemokine receptor 3 (CCR3) plays an important role in the regulation of the migration of eosinophils, a leukocyte population involved 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 environment. In particular, modest variations in the pH and the level of sodium 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 functional level as well; small changes in pH and salt also resulted in striking changes in the migration of primary human eosinophils in vitro. These results reveal that relatively small perturbations in extracellular 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.
Highlights
Eosinophils are involved in many inflammatory pathologies including asthma, urticaria, and hypereosinophilic syndrome [1,2,3]
Binding Affinity as a Function of pH and Salt—We examined the effects of relatively small changes in the extracellular buffer on the binding affinity of eotaxin for chemokine receptor 3 (CCR3)
For eotaxin/CCR3 interactions, we show that ligand binding, Ca2ϩ signaling, and primary eosinophil migration varied over an order of magnitude as a function of net changes of 40 mM (160 –120 mM) sodium chloride and 0.6 pH unit
Summary
Eosinophils are involved in many inflammatory pathologies including asthma, urticaria, and hypereosinophilic syndrome [1,2,3]. The affinity of a specific receptor/ligand interaction can vary depending upon the specific cell type expressing the chemokine receptor, perhaps due to posttranslational modification events or G protein coupling. It appears that cells can modulate their responses to chemokines, but how this is done is not yet clear. We report here that relatively modest changes in pH and salt over a physiologic range can dramatically alter both the binding affinity and signaling efficacy of eotaxin/CCR3 interactions These biochemical changes are mirrored by functional changes induced by eotaxin on primary human eosinophils
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