RESERACH SUMMARY

Chemokines are a family of proinflammatory cytokines that, through interaction with seven transmembrane G protein-coupled receptors, play a key role in numerous biological processes, from organogenesis and leukocyte trafficking to host immune responses. Signalling through chemokine receptors involves ligand-induced conformational changes in the receptor, allowing binding of JAK kinases and interaction with G proteins, initiating signalling cascades that lead to cytoskeletal rearrangement, gene expression, and receptor desensitization via internalization.

Chemokine receptors were thought to exist as isolated entities, allowing a 1:1 interaction with the corresponding ligand as the basic unit that triggers signalling and functional consequences. Chemokine biology is nonetheless more complex than initially predicted, as several studies suggest that chemokines can dimerise and that their receptors are found as dimers and/or higher order oligomers at the cell surface. Receptor oligomerisation might alter G protein specificity, coupling to signalling pathways, attenuate signalling, facilitating synergism between chemokine pairs and allowing GPCR crosstalk. The potential of chemokine receptor oligomerisation greatly increases the number of potential phenotypes, with implications for physiology and pharmacological intervention.

In recent years, we have studied chemokine-induced signalling pathways, including changes in receptor conformation, activation of tyrosine kinases and the various possibilities of chemokine signalling dependent on the cell microenvironment. Using the chemokine receptors CXCR4 and CCR7, we observed differences in coupling to distinct signalling pathways depending on the cell type analyzed. JAK kinases, G proteins and PI3 kinases are essential for some functions but dispensable for others. These effects are not only cell-type specific, but also chemokine receptor-specific; in some cases, there are also differences depending on the chemokine that activates a given receptor.

In previous work, we showed that the ligands for CXCR4 and CCR7 can couple to distinct signalling pathways in tumours and lymphoid cells. Our current research program is related to analysis of chemokine receptor conformations in different cell microenvironments. Using classical biochemical techniques and resonance energy transfer, we are analyzing interactions between chemokine receptors, which can indicate novel, specific activities triggered by chemokines. The main objective is to envisage new ways of modulating chemokine responses that could be therapeutically relevant by promoting or disrupting specific chemokine receptor complexes that indicate specific signalling events and therefore, cell-specific chemokine functions.