CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11.
The chemokine receptor CXCR3 is predominantly expressed on T lymphocytes, and its agonists CXCL9, CXCL10 and CXCL11 are IFN-gamma-inducible chemokines that promote Th1 responses. In contrast, the CCR3 agonists CCL11, CCL24 and CCL26 are involved in the recruitment of cells such as eosinophils and basophils during Th2 responses. Here, we report that although CCL11, CCL24 and CCL26 are neither agonists nor antagonists of CXCR3, CCL11 binds with high affinity to CXCR3. This suggests that, in vivo, CXCR3 may act as a decoy receptor, sequestering locally produced CCL11. We also demonstrate that the CXCR3 ligands inhibit CCR3-mediated functional responses of both human eosinophils and CCR3 transfectants induced by all three eotaxins, with CXCL11 being the most efficacious antagonist. The examination of CCR3-CCR1 chimeric constructs revealed that CCL11 and CXCL11 share overlapping binding sites contained within the CCR3 extracellular loops, a region that was previously shown to be essential for effective receptor-activation. Hence, eosinophil responses mediated by chemokines acting at CCR3 may be regulated by two distinct mechanisms: the antagonistic effects of CXCR3 ligands and the sequestration of CCL11 by CXCR3-expressing cells. Such interplay may serve to finely tune inflammatory responses in vivo.
Xanthou
Georgina
G
Leukocyte Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London, GB.
Duchesnes
Cécile Emmanuelle
CE
Williams
Timothy John
TJ
Pease
James Edward
JE
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D048429:Cell Size; D054423:Chemokine CCL24; D000075906:Chemokine CCL26; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D004804:Eosinophils / Q000166:cytology / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007700:Kinetics; D007962:Leukocytes / Q000276:immunology; D008024:Ligands; D051379:Mice; D018448:Models, Immunological; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C515484:CCL24 protein, human; C120429:CCL26 protein, human; C515350:CCR3 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; C515485:Ccl24 protein, mouse; C515351:Ccr3 protein, mouse; D054423:Chemokine CCL24; D000075906:Chemokine CCL26; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine