Endogenous ligand bias by chemokines: implications at the front lines of infection and leukocyte trafficking.
Chemokine receptors are a group of homologous seven transmembrane receptors (7TMR) that direct cell migration. Their ligands comprise a family of proteins that share structural, biochemical, and physiological features to govern leukocyte trafficking. Multiple endogenous chemokines with overlapping function have evolved for the majority of chemokine receptors. This duplicity of ligands has traditionally been seen to confer physiologic redundancy, especially as it pertains to chemotaxis mediated through G-protein activation. Yet, several recent reports also suggest that chemokine receptors are capable of differential signaling in a ligand-specific manner. This review will explore emerging concepts related to ligand bias at chemokine receptors. Recent studies show that although the endogenous ligands of CCR7 have apparent equipotency for G-protein signaling, they differentially activate the G-protein coupled receptor kinase (GRK)/β-arrestin system to selectively control receptor desensitization. In contrast, similar studies using endogenous ligands for CCR5, a human immunodeficiency virus (HIV) co-receptor, suggest this receptor is not subject to ligand bias by its principle chemokines. Nonetheless, this receptor does appear to be capable of biased agonism by synthetic chemokine analogues. These observations provide compelling evidence that ligand bias exists both as a naturally relevant and therapeutically important phenomenon. This review will highlight the evidence for differential signaling by CCR7 and CCR5, speculate on the physiologic relevance, and discuss the rationale behind the development of biased agonists for the treatment of HIV infection.