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Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10

Lim, Herman D.; Robert Lane, J.; Canals, Meritxell; Stone, Martin J.

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Herman D. Lim

Associate Professor

Martin J. Stone


Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the same receptor, a phenomenon known as biased agonism. The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism. To systematically characterize these effects, we analysed G protein-and ?-arrestin-mediated signal transduction resulting from stimulation of these receptors by each of their cognate chemokine ligands within the same cellular background. Although the chemokines did not elicit ligand-biased agonism, the three receptors exhibited different arrays of signaling outcomes. Stimulation of CCR4 by either CC chemokine ligand 17 (CCL17) or CCL22 induced ?-arrestin recruitment but not G protein-mediated signaling, suggesting that CCR4 has the potential to act as a scavenger receptor. At CCR7, both CCL19 and CCL21 stimulated G protein signaling and ?-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and ?-arrestin recruitment, whereas CCL28(1-108) was inactive, suggesting that CCL28(4-108) is the biologically relevant form of this chemokine. These comparisons emphasize the intrinsic abilities of different receptors to couple with different downstream signaling pathways. Comparison of these results with previous studies indicates that differential agonism at these receptors may be highly dependent on the cellular context.

Journal Article Type Article
Acceptance Date Apr 15, 2021
Online Publication Date Apr 19, 2021
Publication Date Apr 19, 2021
Deposit Date Nov 19, 2021
Publicly Available Date Nov 19, 2021
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 22
Issue 8
Article Number 4232
Keywords Inorganic Chemistry; Organic Chemistry; Physical and Theoretical Chemistry; Computer Science Applications; Spectroscopy; Molecular Biology; General Medicine; Catalysis
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