D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

Abstract

Chemokines are key regulators of leukocyte migration and play important roles in a number of physiological and pathological immune and inflammatory contexts. In addition to the classical signalling chemokine receptors there has emerged, recently, a new subclass of atypical chemokine receptors. This subfamily is characterised by an apparent lack of signalling and, in some cases, by an ability to internalise and degrade chemokine ligands. This review describes the family of atypical chemokine receptors with particular emphasis on the D6 receptor. The in vitro and in vivo biology of D6 is described, which indicates that D6 is active as a scavenger of inflammatory CC-chemokines and appears to play essential roles in the regulation of inflammatory responses.Key words: Chemokines . Immune regulation . Inflammation IntroductionThe movement of leukocytes during immune and inflammatory responses is a carefully orchestrated process that ensures coordinated cellular migration in response to physiological and pathological cues. Prominent amongst the regulators of leukocyte movement are the members of the chemokine family [1]. Chemokines are small proteins (8-12 kDa) and membership of the chemokine family is defined on the basis of the presence of variations on a conserved cysteine motif in the mature section of the proteins. Chemokines can be assigned to one of four subfamilies according to the specific nature of this motif. The majority of chemokines have four cysteines with 28 chemokines being assigned to the CC family (so-called because of the juxtaposition of the first two cysteine residues) and 16 being assigned to the CXC family (which possess a single variable amino acid between the first two cysteines). The two smaller subfamilies are represented by single members and are the CX3C family (three amino acids between the first two cyteines) and the XC family, which lacks the first and third cyteines seen in the other family members. Much confusion arose in the mid-1990s due to the complex and variable nomenclature used to refer to chemokines. For this reason a systematic nomenclature system has been adopted, which refers to the chemokines as ligands of each of the subfamilies and numbers them according to when their sequences were first deposited in the Genbank databases [2]. Thus, CCL1 is the first CC chemokine to be identified and CCL28 the most recent. Chemokines and their roles in leukocyte migrationFunctionally, chemokines are known to be pleiotropic. However, their main role is in the regulation of leukocyte migration. In this context we can define chemokines as being either homeostatic/ constitutive or inflammatory according to the contexts in which they function [2,3]. Homeostatic chemokinesThe homeostatic chemokines are important for the regulation of basal leukocyte trafficking and regulate processes such as the Mini-Reviewtissue-specific migration of T cells and the homing of DC to draining lymph nodes [4][5][6]. In combination with adhesion molecules, the homeostatic chemokines can form part of a very spec...

The presumed atypical chemokine receptor CXCR7 signals through Gi/o proteins in primary rodent astrocytes and human glioma cells

“…This motif represents a highly conserved region within the second intracellular loop of GPCRs and is assumed to be essential for G protein binding and their subsequent activation. Indeed, several established atypical chemokine receptors such as D6, DARC, and CCX-CKR either lack the DRYLAIV motif or exhibit a modified motif (Graham, 2009). However, other chemokine receptors such as lymphotactin receptors and CXCR6, also showing modifications of the DRYLAIV motif, still signal through G proteins (Thelen and Thelen, 2008).…”

“…The currently available data imply that in contrast to CXCR4, CXCR7 would represent an atypical or scavenger chemokine receptor. Similar to the atypical chemokine receptors, D6 and CCX-CKR (Graham, 2009), CXCR7 contains a modified DRYLAIV motif; this motif is assumed to be essential for G protein binding (Thelen and Thelen, 2008). Moreover, several studies failed to demonstrate CXCR7-dependent activation of G proteins and subsequent Ca 21 -induced chemotaxis (Burns et al, 2006;Levoye et al, 2009;Rajagopal et al, 2010b;Sierro et al, 2007).…”

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

“…To date, no endogenously expressed biased 7TMRs have been described. We speculated that candidates for such receptors are the "decoy receptors," which do not appear to signal through G proteins and are thought to scavenge or internalize ligands or act as coreceptors for other chemokine receptors (7).…”

Potential combinatorial effects of recombinant atypical chemokine receptors in breast cancer cell invasion: A research perspective

“…However, certain chemokines are subject to natural modulation of their concentrations by proteins to which they bind without leading to typical signalling (8). These proteins may be endogenously encoded or expressed by exogenous sources to modulate chemokine functions.…”