title: Chemokine receptor CCR3 function is highly dependent on local pH and ionic strength.
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.
authors.affiliation: Department of Immunobiology, DNAX Research Institute, Palo Alto, California 94304, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Dairaghi
authors.forename: E R
authors.initials: ER
authors.lastname: Oldham
authors.forename: K B
authors.initials: KB
authors.lastname: Bacon
authors.forename: T J
authors.initials: TJ
authors.lastname: Schall
mesh_terms: D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D009994:Osmolar Concentration; D011485:Protein Binding; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D012965:Sodium Chloride; D002118:Calcium