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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.

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(&Delta, 26). We found that, compared to CCL15(&Delta, 26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from &beta, Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(&Delta, 26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(&Delta, 26) also resulted in signaling bias between cAMP inhibition and &beta, Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.

The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms by which the interactions of chemokines with chemokine receptors are regulated, including: selective and competitive binding interactions; genetic polymorphisms; mRNA splice variation; variation of expression, degradation and localization; down-regulation by atypical (decoy) receptors; interactions with cell-surface glycosaminoglycans; post-translational modifications; oligomerization; alternative signaling responses; and binding to natural or pharmacological inhibitors.

Inflammation is the body's response to injury or infection. As early as 2000 years ago, the Roman encyclopaedist Aulus Cornelius Celsus recognised four cardinal signs of this response-redness, heat, swelling and pain; a fifth sign is loss of function.[...].