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Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10

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 agoni...

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Autores principales: Lim, Herman D., Lane, J. Robert, Canals, Meritxell, Stone, Martin J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073111/
https://www.ncbi.nlm.nih.gov/pubmed/33921794
http://dx.doi.org/10.3390/ijms22084232
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author Lim, Herman D.
Lane, J. Robert
Canals, Meritxell
Stone, Martin J.
author_facet Lim, Herman D.
Lane, J. Robert
Canals, Meritxell
Stone, Martin J.
author_sort Lim, Herman D.
collection PubMed
description 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 β-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 β-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 β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-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.
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spelling pubmed-80731112021-04-27 Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10 Lim, Herman D. Lane, J. Robert Canals, Meritxell Stone, Martin J. Int J Mol Sci Article 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 β-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 β-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 β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-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. MDPI 2021-04-19 /pmc/articles/PMC8073111/ /pubmed/33921794 http://dx.doi.org/10.3390/ijms22084232 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lim, Herman D.
Lane, J. Robert
Canals, Meritxell
Stone, Martin J.
Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title_full Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title_fullStr Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title_full_unstemmed Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title_short Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10
title_sort systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073111/
https://www.ncbi.nlm.nih.gov/pubmed/33921794
http://dx.doi.org/10.3390/ijms22084232
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